CD15+ Bone Marrow-derived Cells Are Regulators of Immune Response in ARG1-producing Colorectal Cancer Cells

KENTA MIYOSHI; EIICHI SATO; KENJI KATSUMATA; GENTARO FUKUSHIMA; RYUTARO UDO; EMI NISHIMURA; TOMOYA TAGO; KENTA KASAHARA; JUNICHI MAZAKI; MASANOBU ENOMOTO; TETSUO ISHIZAKI; YUICHI NAGAKAWA; AKIHIKO TSUCHIDA

doi:10.21873/anticanres.15504

Abstract

Background/Aim: Bone marrow-derived cells regulate the antitumor functions of tumor infiltrating lymphocytes (TILs) through arginase 1 (ARG1)-dependent metabolism. This study examines which ARG1-producing lineage is responsible for the inhibitory function of TILs. Materials and Methods: Multiplexed immunohistochemistry was performed for CD11b, CD163, CD68, and CD15, together with ARG1 expression and CD3⁺ TIL infiltration estimation in human colorectal cancer specimens. Results: Stratified survival analyses demonstrated that a large number of CD3⁺ TILs is a favorable prognostic factor in subgroups with a high level of ARG1⁺ infiltration and in the subgroup with a low level of ARG1^– CD15⁺ infiltration. Calculation of the ARG1⁺/ARG1^– ratio demonstrated that CD3⁺ TIL infiltration was prognostic in the subgroup with a low ARG1⁺/ARG1^– ratio for CD15⁺ cells, contrary to other lineages. Conclusion: Tumor infiltrating CD15⁺ cells, the majority of which show polymorphonuclear features, are responsible for the ARG1-dependent T-cell dysfunction in human colorectal cancer.

Key Words:

Colorectal cancer is a common type of malignancy worldwide. Early-stage colorectal cancers are curatively resectable and have a favorable prognosis, whereas advanced cancers require multidisciplinary therapies to achieve favorable results (1-3). Various chemotherapeutic modalities in combination with molecular targeted therapies, such as those targeting epidermal growth factor receptor (4) or vascular endothelial growth factor (5) have been attempted, and more recently, immunotherapy (6) has also been attempted, but a substantial number of patients are refractory to such treatment modalities.

It is now widely recognized that characteristics of the tumor microenvironment (TME) of individual cancers affect their biological behavior and response to treatment (7). In colorectal cancer, it has been recognized from the 1980s that marked immune/inflammatory cell infiltration is associated with a favorable prognosis (8). Among the various types of immune/inflammatory cells in the TME, T-cell infiltration has been clarified to be associated with the prognosis of cancer patients (9-11). The recent success of immune checkpoint inhibitor therapy for various cancers, including colorectal cancer with mismatch repair deficiency (6, 12, 13), provides another line of evidence that the local immune response defines the biological behavior of cancers. Furthermore, several attempts, such as classification using “immunoscore” (14) have been made to predict patient prognosis and the therapeutic effects of treatments more accurately than conventional staging methods, by considering the level of infiltration of tumor-infiltrating lymphocytes (TILs).

A variety of suppressive or regulatory immune cells, such as regulatory T cells (15), inhibitory subtypes of bone marrow-derived cells, including M2-like macrophages (16), bone marrow-derived suppressor cells (MDSCs) (17), and granulocytes (18) simultaneously infiltrate cancer tissue together with effector lymphocytes. It is assumed that these suppressive cells are responsible for the lack of response to checkpoint inhibitor therapies in some cancer patients (19).

The suppression of cytotoxic lymphocyte activity by bone marrow-derived cells is mediated by L-arginine metabolism in the TME. Stimulation by Th2 cytokines, such as interleukin (IL)-4, IL-13, and transforming growth factor beta induces the production of arginase 1 (ARG1), and suppresses inducible nitric oxide synthase (iNOS), which is associated with cytotoxic function (20, 21). The consumption of L-arginine by ARG1 in the TME results in T-cell inactivation by the inhibition of CD3ζ chain expression on T cells (22, 23).

Many types of myeloid-derived cells express functional ARG1 (24), although the specific ARG1-producing cell lineages responsible for the inhibitory effects against cytotoxic T-cell reactions in the TME have not been clarified to date. In this study, we performed fluorescent multiplex immunohistochemistry on surgically resected human colorectal cancer specimens to investigate the effects of representative ARG1-producing cell lineages, including CD11b⁺, CD163⁺, CD68⁺, and CD15⁺ cells, on the association between CD3⁺ T-lymphocyte infiltration and patient prognosis.

Materials and Methods

Patients. Under approval of the institutional ethics committee, a series of surgically resected colorectal carcinoma specimens and clinical records were collected retrospectively from patients who consulted the Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, between 2005 and 2014. Among the consecutive cases, patients with early stage cancers (Stage 0 and Stage I) and advanced Stage IV cancers were excluded, and 106 Stage II and Stage III patients were enrolled in this study. A summary of the characteristics of the patients are shown in Table I.

View this table:

Table I.

Clinical characteristics of the patients.

Multiplex immunohistochemistry. Formalin-fixed and paraffin-embedded specimens containing the largest cut surface of the tumor were used. Multiplex fluorescent immunohistochemistry was performed by the Tyramide Signal Amplification method using Opal fluorophore reagents (Opal 520, Opal 540, Opal 570, Opal 620, Opal 650, and Opal 690, Akoya Biosciences, Marlboro, MA, USA) according to the manufacturer’s instructions. The primary antibodies used were anti-human CD3 (rabbit monoclonal, clone SP7, Abcam, Cambridge, UK), anti-human CD11b (rabbit monoclonal, clone EP1345Y, Abcam), anti-human CD15 (rabbit monoclonal, clone SP192, Abcam), anti-human CD68 (mouse monoclonal, clone PG-M1, Abcam), anti-human CD163 (mouse monoclonal, clone 10D6, Thermo Fisher Scientific, Waltham, MA, USA), and anti-human arginase I (mouse monoclonal, clone C-2, Santa Cruz Biotechnology, Dallas, TX, USA). A horseradish peroxidase-labeled secondary detection system (EnVision plus, DAKO, Glostrup, Denmark) was used as a catalyst for fluorophore-conjugated tyramide. High pH Target Retrieval Solution (DAKO) was used for primary antigen heat retrieval, and Immunoactive Retrieval Buffer (pH6, Matsunami Glass, Osaka, Japan) was used for antibody stripping.

Quantitative imaging analyses. Fluorescent tissue images were captured from 3 randomly selected high-power fields (669×500 μm) containing cancer cell nests of each specimen, using an automated imaging system (Vectra ver. 3.0, Akoya Biosciences). An image analyzing software program (InForm ver. 2.4.8, Akoya Biosciences) was used to divide images into tissue frameworks (tumor nest and stromal region) and to segment tissue into each cell. Using an analytic software program (Spotfire, TIBCO, Palo Alto, CA), the cutoff value of each fluorescent signal was determined, and the number of immune cells with a specific phenotype was counted.

Statistical analyses. Considering the rightward skewed distribution of the immune cell count, the lower quartile value was used as the cutoff point for grading. Statistical analyses were performed using SPSS Statistics ver. 22 (IBM, Armonk, NY). A p-value of less than 0.05 was considered to indicate a statistically significant difference between groups.

Results

Fluorescent signal detection. CD3 and the various bone marrow-derived cell markers were all detectable by fluorescent multiplex immunohistochemistry. Representative images are shown in Figure 1. The majority of CD11b⁺ cells were mononuclear, but some multinucleated CD11b⁺ cells were also observed. CD68⁺ cells and CD163⁺ cells showed a mononuclear morphology. Most of the CD15⁺ cells demonstrated polymorphonuclear features. Some of the CD11b⁺ cells showing mononuclear features, co-expressed CD15.

Figure 1.

Representative multiplexed labeling images. (A) CD3⁺ lymphocyte infiltration (green) was clearly detectable in cancer tissues. The inset is a bright-field converted image. (B) CD11b⁺, (C) CD68⁺, (D) CD163⁺, and (E) CD15⁺ cell infiltration (green) was also evaluated together with simultaneous ARG1 expression (red). Insets are bright-field converted images. Note the mononuclear morphology of CD68⁺ and CD163⁺ cells and the polynuclear characteristics of CD15⁺ cells. CD11b⁺ cells are predominantly mononuclear, with some polynuclear cells. (F) Multinuclear CD11b⁺ cells often coexpress CD15 (CD11b in green and CD15 in red). Bar=25 μm. The color tones of the fluorescent signals were schematically adjusted by a software program.

Prognostic significance of CD3⁺ intratumoral lymphocytes. A larger number of infiltrating CD3⁺ T cells was associated with a more favorable overall survival of patients (Figure 2A). To analyze the spatial features of the cancer tissue, CD3⁺ lymphocyte infiltration in the cancer cell nest (intratumoral) and in the stromal area was then separately evaluated. Marked intratumoral CD3⁺ lymphocyte infiltration was associated with a favorable overall prognosis (Figure 2B), whereas the amount of stromal CD3⁺ lymphocytes did not significantly correlate with the overall survival of patients (Figure 2C). Similar results were observed for disease-free survival (data not shown).

Figure 2.

Prognostic significance of CD3⁺ TILs. (A) A higher number of CD3⁺ TILs was significantly associated with a more favorable overall prognosis. Analysis considering the spatial distribution of TILs demonstrated that (B) a higher amount of intratumoral CD3⁺ TILs correlated with a more favorable prognosis, although (C) stromal CD3⁺ TILs were not significantly associated with overall survival. TIL: Tumor infiltrating lymphocytes.

Immunomodulatory features of arginase 1-positive bone marrow-derived cells. We next aimed to evaluate the effects of stromal bone marrow-derived cell infiltration on the prognostic effects of intratumoral CD3⁺ T-cell infiltration. In the tumor groups with a high number of infiltrating CD11b⁺, CD163⁺, and CD68⁺ bone marrow-derived cells, intratumoral CD3⁺ T-cell infiltration was associated with a favorable prognosis; however, intratumoral CD3⁺ T-cell infiltration was not significantly associated with patient prognosis in the groups with a low number of these bone marrow-derived cells (Figure 3). In CD15⁺ cells, although the difference was not statistically significant, a similar trend was observed (Figure 3). For disease-free survival, similar results were also obtained and a significant difference was also confirmed for CD15⁺ cells (data not shown). Subsequently, ARG1 expression by these stromal bone marrow-derived cells, and its effects on the association between intraepithelial CD3⁺ T-cell infiltration and prognosis were analyzed. First, all stromal ARG1⁺ cells together, regardless of their cell lineage, were evaluated. The amount of intraepithelial CD3⁺ T-cell infiltration significantly correlated with prognosis in the tumor subgroup with a high level of stromal ARG1⁺ cell infiltration, whereas such an association was not observed in the tumor subgroup with a small number of stromal ARG1⁺ cells (data not shown). In each tumor subgroup with a high level of ARG1⁺CD11b⁺, ARG1⁺CD163⁺, ARG1⁺CD68⁺, and ARG1⁺CD15⁺ cell infiltration, intratumoral CD3⁺ cell infiltration was associated with favorable overall survival, whereas such an association between survival and CD3⁺ lymphocyte infiltration was not confirmed in the tumor subgroup with a low number of ARG1⁺ bone marrow-derived cells (Figure 4). Similar results were also obtained for disease-free survival (data not shown). Next, the ARG1^– counterparts of these cell lineages were analyzed in a similar manner. Regarding the ARG1^– counterparts of CD11b⁺ and CD163⁺ in the subgroup with a high level of ARG1^– cell infiltration, prognosis correlated with the number of infiltrating CD3⁺ intratumoral T-cells (Figure 5). Regarding ARG^– CD68⁺ cells, its amount did not affect the correlation between CD3⁺ TIL and overall survival (Figure 5). In each of the tumor subgroups with a low number of ARG1^–CD11b⁺, ARG1^–CD163⁺, and ARG1^–CD68⁺ infiltrating cells, no significant correlation between CD3⁺ TILs and overall survival were observed (Figure 5). In contrast, in the tumor subgroup with a high number of stromal ARG1^–CD15⁺ cells, no significant correlation between CD3 intratumoral lymphocyte infiltration and overall survival was detected, whereas CD3 intratumoral lymphocyte infiltration was found to associate with a favorable overall survival in the tumor subgroup with a lower number of stromal ARG1^–CD15⁺ infiltrating cells (Figure 5). Similar results were also obtained for disease-free survival (data not shown). These results suggested that ARG1 expression in CD15⁺ cells may have a different effect on CD3⁺ TILs than ARG1 expression in CD11b⁺, CD68⁺, and CD163⁺ cells. Then, to confirm the effect of ARG1 expression on CD15⁺ cells, we calculated the ratio of ARG1⁺/ARG1^– cells among CD15⁺ cells (Figure 6). As 10% of the samples had no ARG1^–CD15⁺ cell infiltration in the stromal area, CD15⁺ cell infiltration in the entire tumor tissue was evaluated to calculate the ratio. In the tumor subgroup with a high ARG1⁺/ARG1^– ratio among the CD15⁺ cells, the number of infiltrating CD3⁺ lymphocytes did not correlate with prognosis. In contrast, in the tumor subgroup comprising CD15⁺ cells that were predominantly ARG^–, a higher number of CD3⁺ T-cell infiltration was associated with favorable overall survival. Similar analyses regarding ARG1 expression in CD163⁺, CD68⁺, and CD11b⁺ cells demonstrated contradictory results to CD15⁺ cells (Figure 6). In the tumor subgroups of CD163⁺, CD68⁺, and CD11b⁺ cells that were predominantly ARG1⁺, marked CD3⁺ T-cell infiltration was associated with favorable survival, whereas such a significant association with prognosis was not observed in the tumor subgroups of CD163⁺, CD68⁺, and CD11b⁺ cells that were predominantly ARG1^–. Identical results were obtained regarding disease-free survival (data not shown).

Figure 3.

Effects of bone marrow-derived cell lineages on the prognostic effects of intratumoral CD3⁺ TILs. In the tumor subgroups with a high number of infiltrating (A) CD11b⁺, (C) CD163⁺, and (E) CD68⁺ cells, a higher number of CD3⁺ TILs was significantly associated with a more favorable overall prognosis. On the other hand, in the tumor subgroups with a low number of infiltrating (B) CD11b⁺, (D) CD163⁺, and (F) CD68⁺ cells, the number of infiltrating CD3⁺ TILs was not a prognostic factor. A similar trend was observed in the tumor subgroups with a (G) high and (H) low number of infiltrating CD15⁺ cells, although the difference was not statistically significant. TIL: Tumor infiltrating lymphocytes.

Figure 4.

Prognostic analysis of CD3⁺ intratumoral TILs stratified by ARG1⁺ bone marrow-derived cell lineages. In the tumor subgroups with a large number of infiltrating ARG1⁺ bone marrow-derived cells, for any lineage, including (A) CD11b⁺, (C) CD163⁺, (E) CD68⁺, and (G) CD15⁺, the infiltration of intratumoral CD3⁺ TILs was favorably prognostic. On the other hand, the infiltration of intratumoral CD3⁺ TILs was not significantly prognostic in the tumor subgroups with a small number of infiltrating ARG1⁺ cells among these cell lineages (B, D, F, H). TIL: Tumor infiltrating lymphocytes.

Figure 5.

Prognostic analysis of intratumoral CD3⁺ TILs stratified by ARG1(–) bone marrow-derived cell lineages. Intratumoral infiltration of CD3⁺ TILs was a favorable prognostic factor for the overall survival of tumor subgroups with a high number of infiltrating (A) ARG1^–CD11b⁺ or (C) ARG1^–CD163⁺ cells. In the tumor subgroups with a low number of infiltrating (B) ARG1^–CD11b⁺ or (D) ARG1^–CD163⁺ cells, intratumoral infiltration of CD3⁺ TILs did not significantly correlate with overall survival. Inversely, for CD15⁺ cells, intratumoral infiltration of CD3⁺ TILs was prognostic in the tumor subgroup with (H) a small number of ARG1^–CD15⁺ cells, whereas such prognostic significance was not observed in the tumor subgroup with (G) high ARG1^–CD15⁺ cell infiltration. In the tumor subgroups stratified by the amount of ARG1^– CD68⁺ cell infiltration, the infiltration of CD3⁺ TILs showed no significant correlation with overall survival time, regardless of the amount of ARG1^–CD68⁺ cell infiltration (E, F). TIL: Tumor infiltrating lymphocytes.

Figure 6.

Prognostic analysis of intratumoral CD3⁺ TILs stratified by ARG1⁺/ARG1^– ratio in various bone marrow-derived cell lineages. Intratumoral infiltration of CD3⁺ TILs was a favorable prognostic factor for overall survival in tumor subgroups with a high ARG1⁺/ARG^– ratio in (A) CD11b⁺, (C) CD163⁺, and (E) CD68⁺ cell lineages, whereas the infiltration of CD3⁺ TILs did not significantly correlated with overall survival in the tumor subgroups with a low ARG1⁺/ARG1^– ratio in these cell lineages (B, D, F). In contrast, for the CD15⁺ lineage, intratumoral infiltration of CD3⁺ TILs was prognostic in the tumor subgroup with (H) a low ARG1⁺/ARG1^– ratio. In the tumor subgroupwith (G) a high ARG1⁺/ARG1^– ratio among the CD15⁺ cell lineages, intratumoral infiltration of CD3⁺ TILs were not a prognostic factor. TIL: Tumor infiltrating lymphocytes.

Discussion

This was an observational study using surgically resected human colorectal cancer specimens. Although this study was based on immunohistochemistry and statistical validation, multiplex immunohistochemistry enabled for accurate counting of target immune/inflammatory cells in strictly identical fields of view. In addition, the analyses were performed using an analytic software program, thus eliminating arbitrary interpretations by the observer. Therefore, we were able to obtain objective results, even though this was an observational immunohistochemical study.

In the present study, similar to preceding studies on colorectal cancer (9-11), favorable overall and disease-free survival times of patients were confirmed in the group with a high level of intratumoral T-cell infiltration. The association between TILs and patient prognosis differed depending on the spatial distribution of TILs. The number of TILs in the tumor nest correlated with patient prognosis, whereas the number of stromal CD3⁺ TILs was not significantly associated with prognosis. Similar features have been reported by immunohistochemical studies of CD8⁺ TILs in colorectal cancer, showing that the number of intratumoral TILs presents the most significant association with patient survival compared to stromal TILs and TILs infiltrating the invasive margin (11). This study confirms the necessity to consider the spatial distribution of TILs for their use as a prognostic or predictive biomarker. Furthermore, it is presumed that intratumoral CD3⁺ TILs are mostly CD8⁺ cytotoxic T lymphocytes, and it can be inferred that the number of CD3⁺ TILs correlates with patient prognosis. On the other hand, stromal CD3⁺ TILs may contain a mixture of a variety of helper subsets, including regulatory T cells which may explain the lack of a significant association between stromal CD3⁺ TIL and prognosis.

The effect of immune/inflammatory cells expressing representative myeloid-derived cell markers on the correlation between intratumoral CD3⁺ TIL infiltration and patient prognosis was evaluated by stratified survival analyses. Among the cell surface markers used in this study, CD11b is a representative cell-surface marker of MDSCs (25, 26). CD15 is a phenotypic marker of so-called “polymorphonuclear (PMN)” leukocytes (25, 26), which are expressed on neutrophils and PMN-MDSCs (27). CD68 is a pan-macrophage marker, and CD163 is a cell-surface marker of M2-like suppressive macrophages (28). Although the expression of each marker is not sufficient to strictly identify the above indicated cell lineages, these markers were used for general categorization.

Bone marrow-derived cells expressing these markers are assumed to include immunosuppressive cells to some extent, although a higher level of CD3⁺ lymphocyte infiltration was associated with a favorable prognosis in the tumor subgroup with a higher number of infiltrating CD11b⁺, CD163⁺, CD68⁺, and CD15⁺ cells. Conversely, in the tumor subgroup with a lower number of infiltrating bone marrow-derived cells, CD3⁺ TIL infiltration was not found to be a significant prognostic factor. These bone marrow-derived cells were then analyzed for concurrent ARG1 expression using the multiple labeling method. A high level of CD3⁺ TIL infiltration was favorably prognostic in the tumor subgroup with a large number of infiltrating ARG1⁺ bone marrow-derived cells of any cell lineage, whereas such prognostic significance of CD3⁺ TILs was not observed in the tumor subgroup with a low number of infiltrating ARG1⁺ cells.

The same analyses were then performed for the ARG1^– counterparts. The number of CD3⁺ TILs was identified as a significantly prognostic factor in the tumor subgroup with a large number of cells of the ARG1^–CD11b⁺ and ARG1^–CD163⁺ lineages, whereas the opposite was observed for the ARG1^–CD15⁺ lineage. CD3⁺ TIL infiltration was prognostic for the tumor subgroup with a low number of infiltrating ARG1^–CD15⁺ cells. Although statistically significant results were not observed for the CD68⁺ lineage, our results suggests that ARG1 expression on CD15⁺ cells, i.e., neutrophils and PMN-MDSCs, has a different effect on CD3⁺ TILs than ARG1 expression on other bone marrow-derived cells.

The large number of infiltrating ARG1⁺ cells of each bone marrow-derived cell lineage is not synonymous with the low number of infiltrating ARG1^– cells. Therefore, we performed similar analyses using the ARG1⁺/ARG1^– ratio of each lineage as a stratification factor. Our results demonstrated that for the CD15⁺ lineage, CD3⁺ TIL infiltration was a significantly favorable factor in the tumor subgroup with a low ARG1⁺/ARG1^– ratio, whereas the number of CD3⁺ TILs were not a significantly prognostic factor in the tumor subgroup with a high ARG1⁺/ARG1^– ratio. Regarding CD11b⁺, CD163⁺, and CD63⁺ lineages, the results were opposite to those of the CD15⁺ lineage, namely, CD3⁺ TIL infiltration was prognostic in the tumor subgroup with a high ARG1⁺/ARG1^– ratio, but not prognostic in the tumor subgroup with a low ARG 1⁺/ARG1^– ratio. These results suggest that local ARG1-dependent immunosuppression in colorectal cancer is mainly regulated by CD15⁺, multinucleated bone marrow-derived cells.

Analyses under simple stratification by each bone marrow-derived cell lineage without using the ARG1⁺/ARG1^– ratio demonstrated that bone marrow-derived cells are enhancing the anti-tumor effect of CD3⁺ TILs. Our results indicated the favorable prognostic significance of CD3⁺ TILs in the subgroups of tumors with a large number of bone marrow-derived cells, including CD15⁺ cells, regardless of ARG1 expression. This appears to contradict the immunosuppressive features of bone marrow-derived cells, although the infiltration of bone marrow-derived cells can be interpreted as part of the immunoinflammatory status of the TME, which is accompanied by the infiltration of various types of immune cells, including inhibitory immune cells. Another possibility underlying this contradiction is the expression of iNOS in bone marrow-derived cells. iNOS is involved in immunostimulatory metabolism, and can be coexpressed with ARG1 (20). The ratio of iNOS-producing cells to ARG1-producing cells in tissues, or the balance of iNOS and ARG1 in individual bone marrow-derived cells may explain this contradiction. In this study, ARG1 expression was measured as a quantitative value, although we categorized ARG1 expression into 2 groups by setting the lowest value at which a positive signal can be detected, to conduct preliminary analyses. Quantitative evaluation to analyze the iNOS/ARG1 ratio in bone marrow-derived cells using continuous quantitative data should be performed in the future.

Regarding the CD11b⁺ lineage, some of the cells appear to have a polymorphonuclear morphology, and co-express CD15, which may correspond to polymorphonucleated MDSCs. Mononuclear CD11b⁺ cells that do not express CD15 and CD15⁺ multinucleated CD11b⁺ cells can be regarded as mononucleated and PMN-MDSCs, respectively. The ARG1⁺CD15⁺ cells detected in this study were assumed to include PMN-MDSCs and neutrophils. The biological function of “polymorphonuclear leukocytes”, including PMN-MDSCs and neutrophils in cancer tissue is remarkably diverse (18). Besides ARG1-dependent suppression, other immunosuppressive mechanisms of neutrophils, such as complement-dependent T-cell suppression (29), have also been focused on. Regarding the diversity of these polymorphonulcear leukocytes, there are conflicting reports on the prognostic significance of tumor-infiltrating neutrophils in colon cancer, with some reports correlating them with a favorable prognosis (30) and others with a poor survival rate (31). Besides immunosuppressive function, polymorphonuclear leukocytes may promote cancer metastasis (32), elucidating diverse functions of polymorphonuclear leukocytes will be exceedingly helpful for the development of cancer therapeutic strategies.

Although it remains difficult to strictly identify human neutrophils and PMN-MDSCs in tissue specimens, the detailed phenotypic characteristics of ARG1⁺CD15⁺ cells in cancer tissue remain an important issue to be clarified.

This study demonstrated that CD15⁺ polymorphonuclear cells in tumor foci are likely to be the mainstay of ARG1-dependent immunosuppression in human colon cancer. Our results highlight the immunosuppressive function of CD15⁺ polymorphonuclear bone marrow-derived cells, and are essential for the development of therapeutic strategies that target this suppressive mechanism.

Conclusion

Among various lineages of bone marrow derived ARG1 producing cells, CD15⁺ polymorphonuclear cells are major suppressor of cytotoxic immune response in human colorectal cancer.

Footnotes

↵* These Authors contributed equally to this study.
Authors’ Contributions
Study concept and design: KM, ES and KK. Data acquisition and analyses: KM, ES, GK, and EM. Sample preparation and organization of clinical information: RU, TT, KK, JM, ME, TI. Drafting of the manuscript: KM, ES. Critical revision of the manuscript: KK, YN, and AT.
Conflicts of Interest
The Authors have no potential conflicts of interest to declare.

Received September 15, 2021.
Revision received November 7, 2021.
Accepted November 8, 2021.

References

↵
1. Chiorean EG,
2. Nandakumar G,
3. Fadelu T,
4. Temin S,
5. Alarcon-Rozas AE,
6. Bejarano S,
7. Croitoru AE,
8. Grover S,
9. Lohar PV,
10. Odhiambo A,
11. Park SH,
12. Garcia ER,
13. Teh C,
14. Rose A,
15. Zaki B and
16. Chamberlin MD
: Treatment of patients with late-stage colorectal cancer: ASCO resource-stratified guideline. JCO Glob Oncol 6: 414-438, 2020. PMID: 32150483. DOI: 10.1200/JGO.19.00367
OpenUrl CrossRef PubMed
1. Hashiguchi Y,
2. Muro K,
3. Saito Y,
4. Ito Y,
5. Ajioka Y,
6. Hamaguchi T,
7. Hasegawa K,
8. Hotta K,
9. Ishida H,
10. Ishiguro M,
11. Ishihara S,
12. Kanemitsu Y,
13. Kinugasa Y,
14. Murofushi K,
15. Nakajima TE,
16. Oka S,
17. Tanaka T,
18. Taniguchi H,
19. Tsuji A,
20. Uehara K,
21. Ueno H,
22. Yamanaka T,
23. Yamazaki K,
24. Yoshida M,
25. Yoshino T,
26. Itabashi M,
27. Sakamaki K,
28. Sano K,
29. Shimada Y,
30. Tanaka S,
31. Uetake H,
32. Yamaguchi S,
33. Yamaguchi N,
34. Kobayashi H,
35. Matsuda K,
36. Kotake K,
37. Sugihara K and Japanese Society for Cancer of the Colon and Rectum
: Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 25(1): 1-42, 2020. PMID: 31203527. DOI: 10.1007/s10147-019-01485-z
OpenUrl CrossRef PubMed
↵
1. Lopes G,
2. Stern MC,
3. Temin S,
4. Sharara AI,
5. Cervantes A,
6. Costas-Chavarri A,
7. Engineer R,
8. Hamashima C,
9. Ho GF,
10. Huitzil FD,
11. Moghani MM,
12. Nandakumar G,
13. Shah MA,
14. Teh C,
15. Manjarrez SEV,
16. Verjee A,
17. Yantiss R and
18. Correa MC
: Early detection for colorectal cancer: ASCO resource-stratified guideline. J Glob Oncol 5: 1-22, 2019. PMID: 30802159. DOI: 10.1200/JGO.18.00213
OpenUrl CrossRef PubMed
↵
1. Douillard JY,
2. Oliner KS,
3. Siena S,
4. Tabernero J,
5. Burkes R,
6. Barugel M,
7. Humblet Y,
8. Bodoky G,
9. Cunningham D,
10. Jassem J,
11. Rivera F,
12. Kocákova I,
13. Ruff P,
14. Błasińska-Morawiec M,
15. Šmakal M,
16. Canon JL,
17. Rother M,
18. Williams R,
19. Rong A,
20. Wiezorek J,
21. Sidhu R and
22. Patterson SD
: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11): 1023-1034, 2013. PMID: 24024839. DOI: 10.1056/NEJMoa1305275
OpenUrl CrossRef PubMed
↵
1. de Gramont A,
2. Van Cutsem E,
3. Schmoll HJ,
4. Tabernero J,
5. Clarke S,
6. Moore MJ,
7. Cunningham D,
8. Cartwright TH,
9. Hecht JR,
10. Rivera F,
11. Im SA,
12. Bodoky G,
13. Salazar R,
14. Maindrault-Goebel F,
15. Shacham-Shmueli E,
16. Bajetta E,
17. Makrutzki M,
18. Shang A,
19. André T and
20. Hoff PM
: Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 13(12): 1225-1233, 2012. PMID: 23168362. DOI: 10.1016/S1470-2045(12)70509-0
OpenUrl CrossRef PubMed
↵
1. Ganesh K,
2. Stadler ZK,
3. Cercek A,
4. Mendelsohn RB,
5. Shia J,
6. Segal NH and
7. Diaz LA Jr.
: Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol 16(6): 361-375, 2019. PMID: 30886395. DOI: 10.1038/s41575-019-0126-x
OpenUrl CrossRef PubMed
↵
1. Swartz MA,
2. Iida N,
3. Roberts EW,
4. Sangaletti S,
5. Wong MH,
6. Yull FE,
7. Coussens LM and
8. DeClerck YA
: Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res 72(10): 2473-2480, 2012. PMID: 22414581. DOI: 10.1158/0008-5472.CAN-12-0122
OpenUrl Abstract/FREE Full Text
↵
1. Jass JR
: Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 39(6): 585-589, 1986. PMID: 3722412. DOI: 10.1136/jcp.39.6.585
OpenUrl Abstract/FREE Full Text
↵
1. Galon J,
2. Costes A,
3. Sanchez-Cabo F,
4. Kirilovsky A,
5. Mlecnik B,
6. Lagorce-Pagès C,
7. Tosolini M,
8. Camus M,
9. Berger A,
10. Wind P,
11. Zinzindohoué F,
12. Bruneval P,
13. Cugnenc PH,
14. Trajanoski Z,
15. Fridman WH and
16. Pagès F
: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795): 1960-1964, 2006. PMID: 17008531. DOI: 10.1126/science.1129139
OpenUrl Abstract/FREE Full Text
1. Pagès F,
2. Berger A,
3. Camus M,
4. Sanchez-Cabo F,
5. Costes A,
6. Molidor R,
7. Mlecnik B,
8. Kirilovsky A,
9. Nilsson M,
10. Damotte D,
11. Meatchi T,
12. Bruneval P,
13. Cugnenc PH,
14. Trajanoski Z,
15. Fridman WH and
16. Galon J
: Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25): 2654-2666, 2005. PMID: 16371631. DOI: 10.1056/NEJMoa051424
OpenUrl CrossRef PubMed
↵
1. Naito Y,
2. Saito K,
3. Shiiba K,
4. Ohuchi A,
5. Saigenji K,
6. Nagura H and
7. Ohtani H
: CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58(16): 3491-3494, 1998. PMID: 9721846.
OpenUrl Abstract/FREE Full Text
↵
1. Le DT,
2. Uram JN,
3. Wang H,
4. Bartlett BR,
5. Kemberling H,
6. Eyring AD,
7. Skora AD,
8. Luber BS,
9. Azad NS,
10. Laheru D,
11. Biedrzycki B,
12. Donehower RC,
13. Zaheer A,
14. Fisher GA,
15. Crocenzi TS,
16. Lee JJ,
17. Duffy SM,
18. Goldberg RM,
19. de la Chapelle A,
20. Koshiji M,
21. Bhaijee F,
22. Huebner T,
23. Hruban RH,
24. Wood LD,
25. Cuka N,
26. Pardoll DM,
27. Papadopoulos N,
28. Kinzler KW,
29. Zhou S,
30. Cornish TC,
31. Taube JM,
32. Anders RA,
33. Eshleman JR,
34. Vogelstein B and
35. Diaz LA Jr.
: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26): 2509-2520, 2015. PMID: 26028255. DOI: 10.1056/NEJMoa1500596
OpenUrl CrossRef PubMed
↵
1. Overman MJ,
2. McDermott R,
3. Leach JL,
4. Lonardi S,
5. Lenz HJ,
6. Morse MA,
7. Desai J,
8. Hill A,
9. Axelson M,
10. Moss RA,
11. Goldberg MV,
12. Cao ZA,
13. Ledeine JM,
14. Maglinte GA,
15. Kopetz S and
16. André T
: Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18(9): 1182-1191, 2017. PMID: 28734759. DOI: 10.1016/S1470-2045(17)30422-9
OpenUrl CrossRef PubMed
↵
1. Galon J,
2. Pagès F,
3. Marincola FM,
4. Angell HK,
5. Thurin M,
6. Lugli A,
7. Zlobec I,
8. Berger A,
9. Bifulco C,
10. Botti G,
11. Tatangelo F,
12. Britten CM,
13. Kreiter S,
14. Chouchane L,
15. Delrio P,
16. Arndt H,
17. Asslaber M,
18. Maio M,
19. Masucci GV,
20. Mihm M,
21. Vidal-Vanaclocha F,
22. Allison JP,
23. Gnjatic S,
24. Hakansson L,
25. Huber C,
26. Singh-Jasuja H,
27. Ottensmeier C,
28. Zwierzina H,
29. Laghi L,
30. Grizzi F,
31. Ohashi PS,
32. Shaw PA,
33. Clarke BA,
34. Wouters BG,
35. Kawakami Y,
36. Hazama S,
37. Okuno K,
38. Wang E,
39. O’Donnell-Tormey J,
40. Lagorce C,
41. Pawelec G,
42. Nishimura MI,
43. Hawkins R,
44. Lapointe R,
45. Lundqvist A,
46. Khleif SN,
47. Ogino S,
48. Gibbs P,
49. Waring P,
50. Sato N,
51. Torigoe T,
52. Itoh K,
53. Patel PS,
54. Shukla SN,
55. Palmqvist R,
56. Nagtegaal ID,
57. Wang Y,
58. D’Arrigo C,
59. Kopetz S,
60. Sinicrope FA,
61. Trinchieri G,
62. Gajewski TF,
63. Ascierto PA and
64. Fox BA
: Cancer classification using the Immunoscore: a worldwide task force. J Transl Med 10: 205, 2012. PMID: 23034130. DOI: 10.1186/1479-5876-10-205
OpenUrl CrossRef PubMed
↵
1. Li C,
2. Jiang P,
3. Wei S,
4. Xu X and
5. Wang J
: Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol Cancer 19(1): 116, 2020. PMID: 32680511. DOI: 10.1186/s12943-020-01234-1
OpenUrl CrossRef PubMed
↵
1. Zhu S,
2. Luo Z,
3. Li X,
4. Han X,
5. Shi S and
6. Zhang T
: Tumor-associated macrophages: role in tumorigenesis and immunotherapy implications. J Cancer 12(1): 54-64, 2021. PMID: 33391402. DOI: 10.7150/jca.49692
OpenUrl CrossRef PubMed
↵
1. Kumar V,
2. Patel S,
3. Tcyganov E and
4. Gabrilovich DI
: The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37(3): 208-220, 2016. PMID: 26858199. DOI: 10.1016/j.it.2016.01.004
OpenUrl CrossRef PubMed
↵
1. Jaillon S,
2. Ponzetta A,
3. Di Mitri D,
4. Santoni A,
5. Bonecchi R and
6. Mantovani A
: Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer 20(9): 485-503, 2020. PMID: 32694624. DOI: 10.1038/s41568-020-0281-y
OpenUrl CrossRef PubMed
↵
1. Duhan V and
2. Smyth MJ
: Innate myeloid cells in the tumor microenvironment. Curr Opin Immunol 69: 18-28, 2021. PMID: 33588308. DOI: 10.1016/j.coi.2021.01.001
OpenUrl CrossRef PubMed
↵
1. Bronte V and
2. Zanovello P
: Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5(8): 641-654, 2005. PMID: 16056256. DOI: 10.1038/nri1668
OpenUrl CrossRef PubMed
↵
1. Gabrilovich DI and
2. Nagaraj S
: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3): 162-174, 2009. PMID: 19197294. DOI: 10.1038/nri2506
OpenUrl CrossRef PubMed
↵
1. Rodriguez PC,
2. Quiceno DG,
3. Zabaleta J,
4. Ortiz B,
5. Zea AH,
6. Piazuelo MB,
7. Delgado A,
8. Correa P,
9. Brayer J,
10. Sotomayor EM,
11. Antonia S,
12. Ochoa JB and
13. Ochoa AC
: Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16): 5839-5849, 2004. PMID: 15313928. DOI: 10.1158/0008-5472.CAN-04-0465
OpenUrl Abstract/FREE Full Text
↵
1. Rodriguez PC,
2. Zea AH,
3. DeSalvo J,
4. Culotta KS,
5. Zabaleta J,
6. Quiceno DG,
7. Ochoa JB and
8. Ochoa AC
: L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 171(3): 1232-1239, 2003. PMID: 12874210. DOI: 10.4049/jimmunol.171.3.1232
OpenUrl Abstract/FREE Full Text
↵
1. Rodriguez PC,
2. Ochoa AC and
3. Al-Khami AA
: Arginine metabolism in myeloid cells shapes innate and adaptive immunity. Front Immunol 8: 93, 2017. PMID: 28223985. DOI: 10.3389/fimmu.2017.00093
OpenUrl CrossRef PubMed
↵
1. Talmadge JE and
2. Gabrilovich DI
: History of myeloid-derived suppressor cells. Nat Rev Cancer 13(10): 739-752, 2013. PMID: 24060865. DOI: 10.1038/nrc3581
OpenUrl CrossRef PubMed
↵
1. Bronte V,
2. Brandau S,
3. Chen SH,
4. Colombo MP,
5. Frey AB,
6. Greten TF,
7. Mandruzzato S,
8. Murray PJ,
9. Ochoa A,
10. Ostrand-Rosenberg S,
11. Rodriguez PC,
12. Sica A,
13. Umansky V,
14. Vonderheide RH and
15. Gabrilovich DI
: Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7: 12150, 2016. PMID: 27381735. DOI: 10.1038/ncomms12150
OpenUrl CrossRef PubMed
↵
1. Dumitru CA,
2. Moses K,
3. Trellakis S,
4. Lang S and
5. Brandau S
: Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol Immunother 61(8): 1155-1167, 2012. PMID: 22692756. DOI: 10.1007/s00262-012-1294-5
OpenUrl CrossRef PubMed
↵
1. Elliott LA,
2. Doherty GA,
3. Sheahan K and
4. Ryan EJ
: Human tumor-infiltrating myeloid cells: Phenotypic and functional diversity. Front Immunol 8: 86, 2017. PMID: 28220123. DOI: 10.3389/fimmu.2017.00086
OpenUrl CrossRef PubMed
↵
1. Emmons TR,
2. Giridharan T,
3. Singel KL,
4. Khan ANH,
5. Ricciuti J,
6. Howard K,
7. Silva-Del Toro SL,
8. Debreceni IL,
9. Aarts CEM,
10. Brouwer MC,
11. Suzuki S,
12. Kuijpers TW,
13. Jongerius I,
14. Allen LH,
15. Ferreira VP,
16. Schubart A,
17. Sellner H,
18. Eder J,
19. Holland SM,
20. Ram S,
21. Lederer JA,
22. Eng KH,
23. Moysich KB,
24. Odunsi K,
25. Yaffe MB,
26. Zsiros E and
27. Segal BH
: Mechanisms driving neutrophil-induced T-cell immunoparalysis in ovarian cancer. Cancer Immunol Res 9(7): 790-810, 2021. PMID: 33990375. DOI: 10.1158/2326-6066.CIR-20-0922
OpenUrl Abstract/FREE Full Text
↵
1. Berry RS,
2. Xiong MJ,
3. Greenbaum A,
4. Mortaji P,
5. Nofchissey RA,
6. Schultz F,
7. Martinez C,
8. Luo L,
9. Morris KT and
10. Hanson JA
: High levels of tumor-associated neutrophils are associated with improved overall survival in patients with stage II colorectal cancer. PLoS One 12(12): e0188799, 2017. PMID: 29211768. DOI: 10.1371/journal.pone.0188799
OpenUrl CrossRef PubMed
↵
1. Rao HL,
2. Chen JW,
3. Li M,
4. Xiao YB,
5. Fu J,
6. Zeng YX,
7. Cai MY and
8. Xie D
: Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients’ adverse prognosis. PLoS One 7(1): e30806, 2012. PMID: 22295111. DOI: 10.1371/journal.pone.0030806
OpenUrl CrossRef PubMed
↵
1. Ten Kate M,
2. Aalbers AG,
3. Sluiter W,
4. Hofland LJ,
5. Sonneveld P,
6. Jeekel J and
7. Van Eijck CH
: Polymorphonuclear leukocytes increase the adhesion of circulating tumor cells to microvascular endothelium. Anticancer Res 27(1A): 17-22, 2007. PMID: 17352210.
OpenUrl PubMed

In this issue

Download PDF

Article Alerts

Email Article

Citation Tools

Reprints and Permissions

Cited By...

Google Scholar

More in this TOC Section

Show more Experimental Studies

Keywords

[1] ↵
Chiorean EG,
Nandakumar G,
Fadelu T,
Temin S,
Alarcon-Rozas AE,
Bejarano S,
Croitoru AE,
Grover S,
Lohar PV,
Odhiambo A,
Park SH,
Garcia ER,
Teh C,
Rose A,
Zaki B and
Chamberlin MD
: Treatment of patients with late-stage colorectal cancer: ASCO resource-stratified guideline. JCO Glob Oncol 6: 414-438, 2020. PMID: 32150483. DOI: 10.1200/JGO.19.00367
OpenUrl CrossRef PubMed

[2] Chiorean EG,

[3] Nandakumar G,

[4] Fadelu T,

[5] Temin S,

[6] Alarcon-Rozas AE,

[7] Bejarano S,

[8] Croitoru AE,

[9] Grover S,

[10] Lohar PV,

[11] Odhiambo A,

[12] Park SH,

[13] Garcia ER,

[14] Teh C,

[15] Rose A,

[16] Zaki B and

[17] Chamberlin MD

[18] Hashiguchi Y,
Muro K,
Saito Y,
Ito Y,
Ajioka Y,
Hamaguchi T,
Hasegawa K,
Hotta K,
Ishida H,
Ishiguro M,
Ishihara S,
Kanemitsu Y,
Kinugasa Y,
Murofushi K,
Nakajima TE,
Oka S,
Tanaka T,
Taniguchi H,
Tsuji A,
Uehara K,
Ueno H,
Yamanaka T,
Yamazaki K,
Yoshida M,
Yoshino T,
Itabashi M,
Sakamaki K,
Sano K,
Shimada Y,
Tanaka S,
Uetake H,
Yamaguchi S,
Yamaguchi N,
Kobayashi H,
Matsuda K,
Kotake K,
Sugihara K and Japanese Society for Cancer of the Colon and Rectum
: Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 25(1): 1-42, 2020. PMID: 31203527. DOI: 10.1007/s10147-019-01485-z
OpenUrl CrossRef PubMed

[19] Hashiguchi Y,

[20] Muro K,

[21] Saito Y,

[22] Ito Y,

[23] Ajioka Y,

[24] Hamaguchi T,

[25] Hasegawa K,

[26] Hotta K,

[27] Ishida H,

[28] Ishiguro M,

[29] Ishihara S,

[30] Kanemitsu Y,

[31] Kinugasa Y,

[32] Murofushi K,

[33] Nakajima TE,

[34] Oka S,

[35] Tanaka T,

[36] Taniguchi H,

[37] Tsuji A,

[38] Uehara K,

[39] Ueno H,

[40] Yamanaka T,

[41] Yamazaki K,

[42] Yoshida M,

[43] Yoshino T,

[44] Itabashi M,

[45] Sakamaki K,

[46] Sano K,

[47] Shimada Y,

[48] Tanaka S,

[49] Uetake H,

[50] Yamaguchi S,

[51] Yamaguchi N,

[52] Kobayashi H,

[53] Matsuda K,

[54] Kotake K,

[55] Sugihara K and Japanese Society for Cancer of the Colon and Rectum

[56] ↵
Lopes G,
Stern MC,
Temin S,
Sharara AI,
Cervantes A,
Costas-Chavarri A,
Engineer R,
Hamashima C,
Ho GF,
Huitzil FD,
Moghani MM,
Nandakumar G,
Shah MA,
Teh C,
Manjarrez SEV,
Verjee A,
Yantiss R and
Correa MC
: Early detection for colorectal cancer: ASCO resource-stratified guideline. J Glob Oncol 5: 1-22, 2019. PMID: 30802159. DOI: 10.1200/JGO.18.00213
OpenUrl CrossRef PubMed

[57] Lopes G,

[58] Stern MC,

[59] Temin S,

[60] Sharara AI,

[61] Cervantes A,

[62] Costas-Chavarri A,

[63] Engineer R,

[64] Hamashima C,

[65] Ho GF,

[66] Huitzil FD,

[67] Moghani MM,

[68] Nandakumar G,

[69] Shah MA,

[70] Teh C,

[71] Manjarrez SEV,

[72] Verjee A,

[73] Yantiss R and

[74] Correa MC

[75] ↵
Douillard JY,
Oliner KS,
Siena S,
Tabernero J,
Burkes R,
Barugel M,
Humblet Y,
Bodoky G,
Cunningham D,
Jassem J,
Rivera F,
Kocákova I,
Ruff P,
Błasińska-Morawiec M,
Šmakal M,
Canon JL,
Rother M,
Williams R,
Rong A,
Wiezorek J,
Sidhu R and
Patterson SD
: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11): 1023-1034, 2013. PMID: 24024839. DOI: 10.1056/NEJMoa1305275
OpenUrl CrossRef PubMed

[76] Douillard JY,

[77] Oliner KS,

[78] Siena S,

[79] Tabernero J,

[80] Burkes R,

[81] Barugel M,

[82] Humblet Y,

[83] Bodoky G,

[84] Cunningham D,

[85] Jassem J,

[86] Rivera F,

[87] Kocákova I,

[88] Ruff P,

[89] Błasińska-Morawiec M,

[90] Šmakal M,

[91] Canon JL,

[92] Rother M,

[93] Williams R,

[94] Rong A,

[95] Wiezorek J,

[96] Sidhu R and

[97] Patterson SD

[98] ↵
de Gramont A,
Van Cutsem E,
Schmoll HJ,
Tabernero J,
Clarke S,
Moore MJ,
Cunningham D,
Cartwright TH,
Hecht JR,
Rivera F,
Im SA,
Bodoky G,
Salazar R,
Maindrault-Goebel F,
Shacham-Shmueli E,
Bajetta E,
Makrutzki M,
Shang A,
André T and
Hoff PM
: Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 13(12): 1225-1233, 2012. PMID: 23168362. DOI: 10.1016/S1470-2045(12)70509-0
OpenUrl CrossRef PubMed

[99] de Gramont A,

[100] Van Cutsem E,

[101] Schmoll HJ,

[102] Tabernero J,

[103] Clarke S,

[104] Moore MJ,

[105] Cunningham D,

[106] Cartwright TH,

[107] Hecht JR,

[108] Rivera F,

[109] Im SA,

[110] Bodoky G,

[111] Salazar R,

[112] Maindrault-Goebel F,

[113] Shacham-Shmueli E,

[114] Bajetta E,

[115] Makrutzki M,

[116] Shang A,

[117] André T and

[118] Hoff PM

[119] ↵
Ganesh K,
Stadler ZK,
Cercek A,
Mendelsohn RB,
Shia J,
Segal NH and
Diaz LA Jr.
: Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol 16(6): 361-375, 2019. PMID: 30886395. DOI: 10.1038/s41575-019-0126-x
OpenUrl CrossRef PubMed

[120] Ganesh K,

[121] Stadler ZK,

[122] Cercek A,

[123] Mendelsohn RB,

[124] Shia J,

[125] Segal NH and

[126] Diaz LA Jr.

[127] ↵
Swartz MA,
Iida N,
Roberts EW,
Sangaletti S,
Wong MH,
Yull FE,
Coussens LM and
DeClerck YA
: Tumor microenvironment complexity: emerging roles in cancer therapy. Cancer Res 72(10): 2473-2480, 2012. PMID: 22414581. DOI: 10.1158/0008-5472.CAN-12-0122
OpenUrl Abstract/FREE Full Text

[128] Swartz MA,

[129] Iida N,

[130] Roberts EW,

[131] Sangaletti S,

[132] Wong MH,

[133] Yull FE,

[134] Coussens LM and

[135] DeClerck YA

[136] ↵
Jass JR
: Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 39(6): 585-589, 1986. PMID: 3722412. DOI: 10.1136/jcp.39.6.585
OpenUrl Abstract/FREE Full Text

[137] Jass JR

[138] ↵
Galon J,
Costes A,
Sanchez-Cabo F,
Kirilovsky A,
Mlecnik B,
Lagorce-Pagès C,
Tosolini M,
Camus M,
Berger A,
Wind P,
Zinzindohoué F,
Bruneval P,
Cugnenc PH,
Trajanoski Z,
Fridman WH and
Pagès F
: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795): 1960-1964, 2006. PMID: 17008531. DOI: 10.1126/science.1129139
OpenUrl Abstract/FREE Full Text

[139] Galon J,

[140] Costes A,

[141] Sanchez-Cabo F,

[142] Kirilovsky A,

[143] Mlecnik B,

[144] Lagorce-Pagès C,

[145] Tosolini M,

[146] Camus M,

[147] Berger A,

[148] Wind P,

[149] Zinzindohoué F,

[150] Bruneval P,

[151] Cugnenc PH,

[152] Trajanoski Z,

[153] Fridman WH and

[154] Pagès F

[155] Pagès F,
Berger A,
Camus M,
Sanchez-Cabo F,
Costes A,
Molidor R,
Mlecnik B,
Kirilovsky A,
Nilsson M,
Damotte D,
Meatchi T,
Bruneval P,
Cugnenc PH,
Trajanoski Z,
Fridman WH and
Galon J
: Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25): 2654-2666, 2005. PMID: 16371631. DOI: 10.1056/NEJMoa051424
OpenUrl CrossRef PubMed

[156] Pagès F,

[157] Berger A,

[158] Camus M,

[159] Sanchez-Cabo F,

[160] Costes A,

[161] Molidor R,

[162] Mlecnik B,

[163] Kirilovsky A,

[164] Nilsson M,

[165] Damotte D,

[166] Meatchi T,

[167] Bruneval P,

[168] Cugnenc PH,

[169] Trajanoski Z,

[170] Fridman WH and

[171] Galon J

[172] ↵
Naito Y,
Saito K,
Shiiba K,
Ohuchi A,
Saigenji K,
Nagura H and
Ohtani H
: CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58(16): 3491-3494, 1998. PMID: 9721846.
OpenUrl Abstract/FREE Full Text

[173] Naito Y,

[174] Saito K,

[175] Shiiba K,

[176] Ohuchi A,

[177] Saigenji K,

[178] Nagura H and

[179] Ohtani H

[180] ↵
Le DT,
Uram JN,
Wang H,
Bartlett BR,
Kemberling H,
Eyring AD,
Skora AD,
Luber BS,
Azad NS,
Laheru D,
Biedrzycki B,
Donehower RC,
Zaheer A,
Fisher GA,
Crocenzi TS,
Lee JJ,
Duffy SM,
Goldberg RM,
de la Chapelle A,
Koshiji M,
Bhaijee F,
Huebner T,
Hruban RH,
Wood LD,
Cuka N,
Pardoll DM,
Papadopoulos N,
Kinzler KW,
Zhou S,
Cornish TC,
Taube JM,
Anders RA,
Eshleman JR,
Vogelstein B and
Diaz LA Jr.
: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26): 2509-2520, 2015. PMID: 26028255. DOI: 10.1056/NEJMoa1500596
OpenUrl CrossRef PubMed

[181] Le DT,

[182] Uram JN,

[183] Wang H,

[184] Bartlett BR,

[185] Kemberling H,

[186] Eyring AD,

[187] Skora AD,

[188] Luber BS,

[189] Azad NS,

[190] Laheru D,

[191] Biedrzycki B,

[192] Donehower RC,

[193] Zaheer A,

[194] Fisher GA,

[195] Crocenzi TS,

[196] Lee JJ,

[197] Duffy SM,

[198] Goldberg RM,

[199] de la Chapelle A,

[200] Koshiji M,

[201] Bhaijee F,

[202] Huebner T,

[203] Hruban RH,

[204] Wood LD,

[205] Cuka N,

[206] Pardoll DM,

[207] Papadopoulos N,

[208] Kinzler KW,

[209] Zhou S,

[210] Cornish TC,

[211] Taube JM,

[212] Anders RA,

[213] Eshleman JR,

[214] Vogelstein B and

[215] Diaz LA Jr.

[216] ↵
Overman MJ,
McDermott R,
Leach JL,
Lonardi S,
Lenz HJ,
Morse MA,
Desai J,
Hill A,
Axelson M,
Moss RA,
Goldberg MV,
Cao ZA,
Ledeine JM,
Maglinte GA,
Kopetz S and
André T
: Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18(9): 1182-1191, 2017. PMID: 28734759. DOI: 10.1016/S1470-2045(17)30422-9
OpenUrl CrossRef PubMed

[217] Overman MJ,

[218] McDermott R,

[219] Leach JL,

[220] Lonardi S,

[221] Lenz HJ,

[222] Morse MA,

[223] Desai J,

[224] Hill A,

[225] Axelson M,

[226] Moss RA,

[227] Goldberg MV,

[228] Cao ZA,

[229] Ledeine JM,

[230] Maglinte GA,

[231] Kopetz S and

[232] André T

[233] ↵
Galon J,
Pagès F,
Marincola FM,
Angell HK,
Thurin M,
Lugli A,
Zlobec I,
Berger A,
Bifulco C,
Botti G,
Tatangelo F,
Britten CM,
Kreiter S,
Chouchane L,
Delrio P,
Arndt H,
Asslaber M,
Maio M,
Masucci GV,
Mihm M,
Vidal-Vanaclocha F,
Allison JP,
Gnjatic S,
Hakansson L,
Huber C,
Singh-Jasuja H,
Ottensmeier C,
Zwierzina H,
Laghi L,
Grizzi F,
Ohashi PS,
Shaw PA,
Clarke BA,
Wouters BG,
Kawakami Y,
Hazama S,
Okuno K,
Wang E,
O’Donnell-Tormey J,
Lagorce C,
Pawelec G,
Nishimura MI,
Hawkins R,
Lapointe R,
Lundqvist A,
Khleif SN,
Ogino S,
Gibbs P,
Waring P,
Sato N,
Torigoe T,
Itoh K,
Patel PS,
Shukla SN,
Palmqvist R,
Nagtegaal ID,
Wang Y,
D’Arrigo C,
Kopetz S,
Sinicrope FA,
Trinchieri G,
Gajewski TF,
Ascierto PA and
Fox BA
: Cancer classification using the Immunoscore: a worldwide task force. J Transl Med 10: 205, 2012. PMID: 23034130. DOI: 10.1186/1479-5876-10-205
OpenUrl CrossRef PubMed

[234] Galon J,

[235] Pagès F,

[236] Marincola FM,

[237] Angell HK,

[238] Thurin M,

[239] Lugli A,

[240] Zlobec I,

[241] Berger A,

[242] Bifulco C,

[243] Botti G,

[244] Tatangelo F,

[245] Britten CM,

[246] Kreiter S,

[247] Chouchane L,

[248] Delrio P,

[249] Arndt H,

[250] Asslaber M,

[251] Maio M,

[252] Masucci GV,

[253] Mihm M,

[254] Vidal-Vanaclocha F,

[255] Allison JP,

[256] Gnjatic S,

[257] Hakansson L,

[258] Huber C,

[259] Singh-Jasuja H,

[260] Ottensmeier C,

[261] Zwierzina H,

[262] Laghi L,

[263] Grizzi F,

[264] Ohashi PS,

[265] Shaw PA,

[266] Clarke BA,

[267] Wouters BG,

[268] Kawakami Y,

[269] Hazama S,

[270] Okuno K,

[271] Wang E,

[272] O’Donnell-Tormey J,

[273] Lagorce C,

[274] Pawelec G,

[275] Nishimura MI,

[276] Hawkins R,

[277] Lapointe R,

[278] Lundqvist A,

[279] Khleif SN,

[280] Ogino S,

[281] Gibbs P,

[282] Waring P,

[283] Sato N,

[284] Torigoe T,

[285] Itoh K,

[286] Patel PS,

[287] Shukla SN,

[288] Palmqvist R,

[289] Nagtegaal ID,

[290] Wang Y,

[291] D’Arrigo C,

[292] Kopetz S,

[293] Sinicrope FA,

[294] Trinchieri G,

[295] Gajewski TF,

[296] Ascierto PA and

[297] Fox BA

[298] ↵
Li C,
Jiang P,
Wei S,
Xu X and
Wang J
: Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol Cancer 19(1): 116, 2020. PMID: 32680511. DOI: 10.1186/s12943-020-01234-1
OpenUrl CrossRef PubMed

[299] Li C,

[300] Jiang P,

[301] Wei S,

[302] Xu X and

[303] Wang J

[304] ↵
Zhu S,
Luo Z,
Li X,
Han X,
Shi S and
Zhang T
: Tumor-associated macrophages: role in tumorigenesis and immunotherapy implications. J Cancer 12(1): 54-64, 2021. PMID: 33391402. DOI: 10.7150/jca.49692
OpenUrl CrossRef PubMed

[305] Zhu S,

[306] Luo Z,

[307] Li X,

[308] Han X,

[309] Shi S and

[310] Zhang T

[311] ↵
Kumar V,
Patel S,
Tcyganov E and
Gabrilovich DI
: The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37(3): 208-220, 2016. PMID: 26858199. DOI: 10.1016/j.it.2016.01.004
OpenUrl CrossRef PubMed

[312] Kumar V,

[313] Patel S,

[314] Tcyganov E and

[315] Gabrilovich DI

[316] ↵
Jaillon S,
Ponzetta A,
Di Mitri D,
Santoni A,
Bonecchi R and
Mantovani A
: Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer 20(9): 485-503, 2020. PMID: 32694624. DOI: 10.1038/s41568-020-0281-y
OpenUrl CrossRef PubMed

[317] Jaillon S,

[318] Ponzetta A,

[319] Di Mitri D,

[320] Santoni A,

[321] Bonecchi R and

[322] Mantovani A

[323] ↵
Duhan V and
Smyth MJ
: Innate myeloid cells in the tumor microenvironment. Curr Opin Immunol 69: 18-28, 2021. PMID: 33588308. DOI: 10.1016/j.coi.2021.01.001
OpenUrl CrossRef PubMed

[324] Duhan V and

[325] Smyth MJ

[326] ↵
Bronte V and
Zanovello P
: Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5(8): 641-654, 2005. PMID: 16056256. DOI: 10.1038/nri1668
OpenUrl CrossRef PubMed

[327] Bronte V and

[328] Zanovello P

[329] ↵
Gabrilovich DI and
Nagaraj S
: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3): 162-174, 2009. PMID: 19197294. DOI: 10.1038/nri2506
OpenUrl CrossRef PubMed

[330] Gabrilovich DI and

[331] Nagaraj S

[332] ↵
Rodriguez PC,
Quiceno DG,
Zabaleta J,
Ortiz B,
Zea AH,
Piazuelo MB,
Delgado A,
Correa P,
Brayer J,
Sotomayor EM,
Antonia S,
Ochoa JB and
Ochoa AC
: Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16): 5839-5849, 2004. PMID: 15313928. DOI: 10.1158/0008-5472.CAN-04-0465
OpenUrl Abstract/FREE Full Text

[333] Rodriguez PC,

[334] Quiceno DG,

[335] Zabaleta J,

[336] Ortiz B,

[337] Zea AH,

[338] Piazuelo MB,

[339] Delgado A,

[340] Correa P,

[341] Brayer J,

[342] Sotomayor EM,

[343] Antonia S,

[344] Ochoa JB and

[345] Ochoa AC

[346] ↵
Rodriguez PC,
Zea AH,
DeSalvo J,
Culotta KS,
Zabaleta J,
Quiceno DG,
Ochoa JB and
Ochoa AC
: L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 171(3): 1232-1239, 2003. PMID: 12874210. DOI: 10.4049/jimmunol.171.3.1232
OpenUrl Abstract/FREE Full Text

[347] Rodriguez PC,

[348] Zea AH,

[349] DeSalvo J,

[350] Culotta KS,

[351] Zabaleta J,

[352] Quiceno DG,

[353] Ochoa JB and

[354] Ochoa AC

[355] ↵
Rodriguez PC,
Ochoa AC and
Al-Khami AA
: Arginine metabolism in myeloid cells shapes innate and adaptive immunity. Front Immunol 8: 93, 2017. PMID: 28223985. DOI: 10.3389/fimmu.2017.00093
OpenUrl CrossRef PubMed

[356] Rodriguez PC,

[357] Ochoa AC and

[358] Al-Khami AA

[359] ↵
Talmadge JE and
Gabrilovich DI
: History of myeloid-derived suppressor cells. Nat Rev Cancer 13(10): 739-752, 2013. PMID: 24060865. DOI: 10.1038/nrc3581
OpenUrl CrossRef PubMed

[360] Talmadge JE and

[361] Gabrilovich DI

[362] ↵
Bronte V,
Brandau S,
Chen SH,
Colombo MP,
Frey AB,
Greten TF,
Mandruzzato S,
Murray PJ,
Ochoa A,
Ostrand-Rosenberg S,
Rodriguez PC,
Sica A,
Umansky V,
Vonderheide RH and
Gabrilovich DI
: Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7: 12150, 2016. PMID: 27381735. DOI: 10.1038/ncomms12150
OpenUrl CrossRef PubMed

[363] Bronte V,

[364] Brandau S,

[365] Chen SH,

[366] Colombo MP,

[367] Frey AB,

[368] Greten TF,

[369] Mandruzzato S,

[370] Murray PJ,

[371] Ochoa A,

[372] Ostrand-Rosenberg S,

[373] Rodriguez PC,

[374] Sica A,

[375] Umansky V,

[376] Vonderheide RH and

[377] Gabrilovich DI

[378] ↵
Dumitru CA,
Moses K,
Trellakis S,
Lang S and
Brandau S
: Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol Immunother 61(8): 1155-1167, 2012. PMID: 22692756. DOI: 10.1007/s00262-012-1294-5
OpenUrl CrossRef PubMed

[379] Dumitru CA,

[380] Moses K,

[381] Trellakis S,

[382] Lang S and

[383] Brandau S

[384] ↵
Elliott LA,
Doherty GA,
Sheahan K and
Ryan EJ
: Human tumor-infiltrating myeloid cells: Phenotypic and functional diversity. Front Immunol 8: 86, 2017. PMID: 28220123. DOI: 10.3389/fimmu.2017.00086
OpenUrl CrossRef PubMed

[385] Elliott LA,

[386] Doherty GA,

[387] Sheahan K and

[388] Ryan EJ

[389] ↵
Emmons TR,
Giridharan T,
Singel KL,
Khan ANH,
Ricciuti J,
Howard K,
Silva-Del Toro SL,
Debreceni IL,
Aarts CEM,
Brouwer MC,
Suzuki S,
Kuijpers TW,
Jongerius I,
Allen LH,
Ferreira VP,
Schubart A,
Sellner H,
Eder J,
Holland SM,
Ram S,
Lederer JA,
Eng KH,
Moysich KB,
Odunsi K,
Yaffe MB,
Zsiros E and
Segal BH
: Mechanisms driving neutrophil-induced T-cell immunoparalysis in ovarian cancer. Cancer Immunol Res 9(7): 790-810, 2021. PMID: 33990375. DOI: 10.1158/2326-6066.CIR-20-0922
OpenUrl Abstract/FREE Full Text

[390] Emmons TR,

[391] Giridharan T,

[392] Singel KL,

[393] Khan ANH,

[394] Ricciuti J,

[395] Howard K,

[396] Silva-Del Toro SL,

[397] Debreceni IL,

[398] Aarts CEM,

[399] Brouwer MC,

[400] Suzuki S,

[401] Kuijpers TW,

[402] Jongerius I,

[403] Allen LH,

[404] Ferreira VP,

[405] Schubart A,

[406] Sellner H,

[407] Eder J,

[408] Holland SM,

[409] Ram S,

[410] Lederer JA,

[411] Eng KH,

[412] Moysich KB,

[413] Odunsi K,

[414] Yaffe MB,

[415] Zsiros E and

[416] Segal BH

[417] ↵
Berry RS,
Xiong MJ,
Greenbaum A,
Mortaji P,
Nofchissey RA,
Schultz F,
Martinez C,
Luo L,
Morris KT and
Hanson JA
: High levels of tumor-associated neutrophils are associated with improved overall survival in patients with stage II colorectal cancer. PLoS One 12(12): e0188799, 2017. PMID: 29211768. DOI: 10.1371/journal.pone.0188799
OpenUrl CrossRef PubMed

[418] Berry RS,

[419] Xiong MJ,

[420] Greenbaum A,

[421] Mortaji P,

[422] Nofchissey RA,

[423] Schultz F,

[424] Martinez C,

[425] Luo L,

[426] Morris KT and

[427] Hanson JA

[428] ↵
Rao HL,
Chen JW,
Li M,
Xiao YB,
Fu J,
Zeng YX,
Cai MY and
Xie D
: Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients’ adverse prognosis. PLoS One 7(1): e30806, 2012. PMID: 22295111. DOI: 10.1371/journal.pone.0030806
OpenUrl CrossRef PubMed

[429] Rao HL,

[430] Chen JW,

[431] Li M,

[432] Xiao YB,

[433] Fu J,

[434] Zeng YX,

[435] Cai MY and

[436] Xie D

[437] ↵
Ten Kate M,
Aalbers AG,
Sluiter W,
Hofland LJ,
Sonneveld P,
Jeekel J and
Van Eijck CH
: Polymorphonuclear leukocytes increase the adhesion of circulating tumor cells to microvascular endothelium. Anticancer Res 27(1A): 17-22, 2007. PMID: 17352210.
OpenUrl PubMed

[438] Ten Kate M,

[439] Aalbers AG,

[440] Sluiter W,

[441] Hofland LJ,

[442] Sonneveld P,

[443] Jeekel J and

[444] Van Eijck CH

Main menu

User menu

Search

CD15⁺ Bone Marrow-derived Cells Are Regulators of Immune Response in ARG1-producing Colorectal Cancer Cells

Abstract

Materials and Methods

Results

Discussion

Conclusion

Footnotes

References

In this issue

Citation Manager Formats

Related Articles

Cited By...

More in this TOC Section

Keywords

Main menu

User menu

Search

CD15+ Bone Marrow-derived Cells Are Regulators of Immune Response in ARG1-producing Colorectal Cancer Cells

Abstract

Materials and Methods

Results

Discussion

Conclusion

Footnotes

References

In this issue

Citation Manager Formats

Jump to section

Related Articles

Cited By...

More in this TOC Section

Keywords

CD15⁺ Bone Marrow-derived Cells Are Regulators of Immune Response in ARG1-producing Colorectal Cancer Cells