Research ArticleExperimental Studies
Open Access

Elevated PD-L1 Expression on Circulating Classical Monocytes Upon Checkpoint Inhibitor Therapy Is Associated With Increased Plasma Interleukin 5 in Patients With Lung Cancer

EVA PROBST, CHRISTIAN IDEL, JONAS FLECKNER, KIRSTIN PLÖTZE-MARTIN, DIRK RADES, SABINE BOHNET, DANIEL DRÖMANN, KARL-LUDWIG BRUCHHAGE, KLAAS FRANZEN and RALPH PRIES
Anticancer Research May 2025, 45 (5) 1915-1925; DOI: https://doi.org/10.21873/anticanres.17569

Abstract

Background/Aim: Lung cancer remains one of the most prevalent cancers worldwide, with high morbidity and mortality rates. Besides established treatment options such as surgery and radio(chemo)therapy, advanced approaches such as anti-programmed death 1 (PD-1)/anti-programmed death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) have been introduced as effective therapeutic options. In this context, PD-L1 expression on myeloid cells has been correlated with poor clinical outcomes in patients with cancer. This study aimed to investigate the influence of ICI treatment on the immunologic alterations of circulating monocyte subsets as potential bioliquid indicators for therapy response assessment in patients with lung cancer.

Materials and Methods: Flow cytometry was employed to analyze the distribution of circulating CD14/CD16 monocyte subsets and the expression of adhesion molecules CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), CX3CR1 (CX3CL1 receptor) and the checkpoint molecule PD-L1 in 22 patients with lung cancer. Furthermore, plasma concentrations of ICI-associated cytokine interleukin (IL-5) were quantified using ELISA the course of therapy.

Results: The study revealed a significant increase in intermediate monocyte abundance, coupled with altered adhesion molecule expression and elevated PD-L1 levels in patients with lung cancer. Moreover, non-responders exhibited significantly increased plasma IL-5 levels after one month of ICI therapy. A significant positive correlation was also observed between plasma IL-5 concentrations and PD-L1 expression on peripheral blood classical monocytes.

Conclusion: The identification of liquid biomarkers, such as peripheral blood monocyte subsets and plasma IL-5 levels, could serve as valuable indicators for ICI therapy decision-making and response prediction in lung cancer patients.

Keywords:

Introduction

Lung cancer (LC) is one of the most common cancers in Germany with high morbidity and mortality rates. In 2020, LC accounted for 13.0% of all new cancer cases in men and 9.8% in women in Germany. LC accounted for 22.2% of all cancer deaths in men and 16.3% in women (1). In the past, the focus of clinical diagnosis was on the histological classification of lung carcinomas into small cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC). NSCLC is the most common subtype with 85%-90% of all LC types (2).

To this day, microscopic histological and cytological examination of the tumor tissue is considered the gold standard of diagnostics (1). While the treatment of stages I and II NSCLC consists of the resection of the tumor tissue and adjuvant therapy, whereas stages III and IV treated with more advanced chemotherapy or/and radiotherapy (3). However, all different traditional chemotherapeutics have shown limits in their efficiency to treat LC, including non-specific targeting, poor bioavailability and drug-resistance (4).

The establishment of molecular examinations and the development of targeting therapies have given new significance to advanced diagnostics as well as immuno-phenotypic and molecular pathological examinations (1). The pathological, immunohistological and molecular examination of the tumor tissue is decisive for the diagnosis, prognosis and choice of therapy. The identification of “programmed death ligand 1” (PDL-1) and “programmed death 1” (PD-1) positive tumor cells is an already established immunohistological diagnosis that is relevant for the choice of therapy (5).

In addition to the established treatment options for LC with chemotherapy, resection and radiation, new research achievements led to the development of novel treatment options such as immune checkpoint inhibitors (ICIs) of checkpoint molecules PD-1and PD-L1 (6-8). Checkpoint molecule PD-L1 is involved in different aspects of immune regulation and T-cell anergy and exhaustion and thus attenuates anti-tumor immune responses (9-12).

PD-L1 is expressed in different types of immune cells including lymphocytes and monocytes (13-16). Myeloid cells in particular are essential regulators of cancer development, where PD-L1 expression has been correlated with poor prognosis of patients with cancer (17-19) and shown to promote cancer progression in lung adenocarcinoma (20).

In this context, radio(chemo)therapy has been observed to increase the abundances of rectal cancer-infiltrating CD8+ T cells and tumor necrosis factor α (TNFα) producing monocytes (21). Basically, circulating monocytes can be subdivided into “classical” monocytes (CD14++CD16−), “intermediate” monocytes (CD14+CD16+) and “non-classical” monocytes (CD14dim+CD16+) (22-24), all of which are capable of developing macrophage morphology and characteristics (25). Our recent data revealed that elevated abundances of non-classical monocytes positively correlated with increased overall monocytic PD-L1 in patients with head and neck cancer (26). However, detailed investigations of the appearances and characteristics of peripheral blood monocytes in patients with LC upon ICI treatment are still missing.

We analyzed the individual distribution of peripheral blood CD14/CD16 monocyte subsets in patients with LC as well as the expression levels of adhesion molecules and chemokine receptors CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), CX3CR1 (CX3CL1 receptor) and checkpoint molecule PD-L1 using flow cytometry, all of which are involved in the cellular adaption to distinct immuno-environmental conditions (27). Furthermore, evaluation of plasma IL-5 levels before and during ICI treatment was carried out, since increased IL-5 secretion levels by THP-1 monocytes have recently been shown in response to anti-PD-L1 ICI treatment (28).

The aim of this study was to investigate the interplay between the individual ICI treatment regimen and the immunologic consequences on circulating monocytes as a potential prognostic biomarker for therapy response assessment in LC patients.

Materials and Methods

Ethics statement and blood collection. In this study, a cohort of 22 patients with LC was analyzed before and after one month and three months of ICI therapy in terms of circulating monocyte subset distribution and cellular characteristics. All patients were examined and treated at the Department of Medical Clinic III, University Hospital Schleswig-Holstein, Campus Luebeck, and have given their written informed consent. The study was approved by the local ethics committee of the University of Luebeck (approval number 16-278) and conducted in accordance with the ethical principles for medical research formulated in the World Medical Association (WMA) Declaration of Helsinki. The clinical data of the patients with LC were obtained from clinical and pathological records and afterward anonymized. TNM stages were assessed according to the 8th edition of the TNM classification for NSCLC. Blood was drawn by venipuncture into a sodium citrate containing S-Monovette (Sarstedt; Nümbrecht, Germany). The clinicopathological characteristics of the patients are listed in Table I.

View this table:
Table I.

Clinicopathological parameters.

Staining of monocyte subsets in whole blood. Whole blood flow cytometric measurements of circulating monocyte subsets was performed as described before using antibodies against the following: CD45-PE, CD14-FITC, CD16-BV-510, HLA-DR-APC-Cy7, CX3CR1-BV421, CD11b-BV421 and CD3-PerCP (all from BioLegend, San Diego, CA, USA) (29).

Cytokine analysis. Plasma concentrations of cytokine IL-5 were assessed in citrate-plasma samples and were determined using enzyme-linked immunosorbent assays (ELISA) according to manufacturer’s protocols (R&D Systems, Minneapolis, MN, USA).

Statistical analysis. Statistical analyses were performed with GraphPad Prism Version 7.0f (GraphPad Software, Inc., San Diego, CA, USA). The mean and standard error of the mean (SEM) are presented. The differences between groups were determined after testing for normal distribution and applying parametric (student’s t-Test), or non–parametric one-way Anova with Bonferroni post hoc test. The correlation between parameters was calculated using multivariate regression with the Pearson correlation coefficient. p<0.05 (*), p<0.01 (**), and p<0.001 (***). Additional statistical details are given in the respective figure legends, when appropriate.

Results

Monocyte subset distribution in patients with LC. Individual abundances of peripheral blood monocyte subsets and associated expression levels of different adhesion molecules upon anti-PD-L1 checkpoint inhibitor therapy of patients with LC were carried out via whole blood flow cytometric measurements as described before (29) (Figure 1).

Figure 1.
Figure 1.

Whole blood measurements of peripheral blood monocyte subsets. (A) Representative example gating scheme of monocyte subset analysis with regard to the forward scatter (FSC)/sideward scatter (SSC) characteristics and the CD14/CD16 expression levels. (B) Percentages of circulating classical (CM), intermediate (IM) and non-classical monocytes (NCM) in the peripheral blood of patients with lung cancer (LC) compared to healthy donors (HD) and during the course of anti-PD-L1 ICI therapy (pre therapy, post one month, post three months). **p<0.01; ***p<0.001.

From our initial cohort of 22 patients with LC before PD1/PD-L1 checkpoint inhibitor treatment, we were able to investigate 18 patients after approximately one month of therapy and 13 after about three months of therapy, because clinical condition of some patients did not allow further treatment. Data revealed significantly increased abundances of intermediate monocytes (IM) accompanied with significantly decreased abundances of non-classical monocytes (NCM) in patients with LC compared to healthy donors. No significant differences were observed between the pre- and post-treatment situation (Figure 1).

Monocytic adhesion molecules in patients with LC. Circulating monocyte subsets from patients with LC were analyzed with regard to expression levels of adhesion molecules CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), and CX3CR1 (CX3CL1 receptor) using flow cytometry and compared to healthy donors (Figure 2).

Figure 2.
Figure 2.

Adhesion molecules CD11a, CD11b, CD11c, and CX3CR1 on monocyte subsets (CM: classical monocytes; IM: intermediate monocytes; NCM: non-classical monocytes) of patients with lung cancer (LC) compared to healthy donors (HD). *p<0.05. MFI: Mean fluorescence intensity.

Measurements revealed significantly increased expression levels of adhesion molecule CD11a on non-classical monocytes (p=0.0039) and a significantly increased expression of CD11b on intermediate monocytes (p=0.0241) in patients with LC compared to healthy donors. Furthermore, expression of CD11c was found to be significantly elevated on classical (p=0.0476) and non-classical (p=0.0140) monocytes in patients with LC compared to healthy donors, but no significant differences were measured concerning expression levels of adhesion marker CX3CR1 (Figure 2). Overall, no significant differences of the analyzed adhesion molecules were observed between the pre- and post-treatment situation (data not shown).

Plasma levels of cytokine interleukin-5 in patients with LC. It has recently been shown in vitro that PD1/PD-L1 checkpoint inhibitors triggered a significantly increase in the levels of IL-5 secretion by THP-1 monocytes (28). Thus, cytokine IL-5 caught our particular interest, also because it has recently been suggested as a potential novel indicator for ICI therapy response (30). In order to quantify the plasma IL-5 levels in our patient cohort during the course of ICI therapy, ELISA measurements were performed. Data revealed significantly increased plasma IL-5 levels (pg/ml) in patients with LC after one month of ICI therapy compared to healthy donors (Figure 3A).

Figure 3.
Figure 3.

Plasma IL-5 in patients with lung cancer before (pre) and upon one month and three-month immune check point inhibitor (ICI) therapy. (A) ELISA measurements reveal significantly increased interleukin IL-5 levels (pg/ml) in patients with lung cancer (LC) after one month of ICI therapy compared to healthy donors (HD). (B) Subdivision of our patient cohort reveals increased IL-5 levels (p=0.0727) in therapy non-responders (non-resp.) compared and responders (resp.) before ICI therapy (pre). ns: not significant; *p<0.05; **p<0.01.

Furthermore, the patient cohort was subdivided in ICI responders and non-responders with regard to the individual radiographic improvement. Data revealed initially slightly increased IL-5 levels in non-responders compared to healthy donors (p=0.0614) and responders (p= 0.0759) and significantly increased IL-5 levels in non-responders after one month of ICI therapy compared to healthy donors (Figure 3B).

Due to the potential association of cytokine IL-5 secretion and checkpoint molecule PD-L1 related therapy response in patients with LC, PD-L1 expression levels on peripheral blood monocyte subsets were analyzed in our patient cohort before and during the course of ICI treatment compared to healthy donors. Data revealed significantly increased PD-L1 expression levels on classical and intermediate monocytes in patients with LC and, moreover, there were further significantly increasing PD-L1 expression levels on classical monocytes upon three months of ICI treatment compared to the pre therapy situation (Figure 4). Correlation analyses revealed no significant relations between plasma IL-5 concentrations and the measured abundances of circulating monocyte subsets. Of note, a significant positive correlation (p= 0.0180) between plasma IL-5 and PD-L1 expression on classical monocytes in patients with LC upon one month of ICI treatment, which indicates an association of these two molecular bioliquid parameters during the course of ICI therapy (Figure 5).

Figure 4.
Figure 4.

Flow cytometric analysis of PD-L1 on peripheral blood monocyte subsets. (A) PD-L1 expression levels on circulating classical (CM) and intermediate (IM) monocytes (NCM) are significantly increased compared to healthy donors (HD). Furthermore, PD-L1 expression levels on classical monocytes are significantly increased in response to three months of ICI therapy compared to the pre therapy situation. **p<0.01; ***p<0.001. MFI: Mean fluorescence intensity.

Figure 5.
Figure 5.

Correlation analysis between the percentages of circulating classical (CM), intermediate (IM) and non-classical monocytes (NCM) in patients with lung cancer and (A) corresponding PD-L1 expression levels and (B) corresponding plasma interleukin IL-5 concentrations (pg/ml) of patients with lung cancer in response to one-month immune check point (ICI) treatment. The correlation coefficient (r) and p-values are given for each correlation. p<0.05 was considered as significant. MFI: Mean fluorescence intensity.

Discussion

Different studies on human cancers have provided evidence that peripheral blood monocyte subsets contribute to both pro- and anti-tumoral immune responses (31-33). In this context, it is well known that circulating monocytes are a major source of immune regulating cytokines and they themselves are also influenced by various tumor derived factors in the blood stream (34, 35).

Our data revealed significantly increased abundances of intermediate monocytes (IM) accompanied with significantly decreased abundances of non-classical monocytes (NCM) in patients with LC compared to healthy donors, but no significant changes during the course of therapy within the observation period of three months. Furthermore, our data revealed significantly increased pre-therapeutic expression levels of adhesion molecules CD11a, CD11b and CD11c on certain monocyte subsets from patients with LC compared to healthy donors. Integrins CD11a and CD11b are well established leukocyte adhesion molecules, that are expressed on dendritic cells, granulocytes and monocytes and can recognize different ligands such as complement factors or lipopolysaccharide (36, 37). They are essentially involved in the adhesion of monocytes to the blood vessel wall and thus contribute to the cellular extravasation (38). No significant influence of ICI treatment on adhesion molecule expression levels was detected within the observation period of three months.

In addition, we observed significantly increased secretion levels of plasma IL-5 in non-responding patients with LC after one month of ICI treatment compared to healthy donors as well as a significant correlation between monocytic IL-5 secretion and PD-L1 expression.

These data corroborate earlier in vitro measurements of increased IL-5 secretion levels by THP-1 monocytes upon stimulation with different anti-PD-1/anti-PD-L1 checkpoint inhibitors (28). Furthermore, it has been shown in patients with breast cancer that IL-5-producing CD4+ T cells and eosinophils cooperate to enhance the response to ICI therapeutic approaches (39).

Besides monocytes, IL-5 is mainly produced by T cells, granulocytes, and natural helper cells. In patients with NSCLC, plasma IL-5 levels have been shown to be closely associated with tumor burden, likely due to increased levels of tumor-infiltrating IL-5-producing cells (30). It has been shown in lung tumor metastasis that innate IL-5-producing cells were increased in response to tumor invasion, and their regulation of eosinophils is critical for the suppression of tumor metastasis. Accordingly, it could be shown that exogenous IL-5 treatment resulted in suppressed tumor metastasis and augmented eosinophil infiltration (40). However, our data suggest an association between lower initial plasma IL-5 levels and a favorable response to anti-PD-L1 therapy, aligning with recent findings that patients with NSCLC with initially decreased IL-5 levels experienced positive clinical outcomes with anti-PD-1 therapy (30).

In summary, a higher tumor burden seems to be associated with higher levels of tumor-infiltrating IL-5 producing cells and with increased IL-5 levels upon anti-PD-1/PD-L1 ICI treatment. However, despite the potential anti-tumor activity of IL-5, our data suggest that patients with NSCLC with a lower tumor burden and accordingly lower IL-5 levels still have a better prognosis and a better response to ICI therapy.

For a successful ICI treatment of patients with cancer, it is crucial to identify easy to handle prognostic markers for therapy decision making and response prediction. A significant correlation was observed between PD-L1 expression on peripheral blood monocytes and plasma IL-5 levels, suggesting their potential as indicators for therapy response and individual immunologic status.

An acknowledged limitation of our study is the relatively small number of patients. Therefore, investigations on larger patient cohorts are required to elucidate the meaningfulness of these potential bioliquid indicators for checkpoint-inhibitor therapy in patients with LC.

Acknowledgements

The Authors are grateful to all members of the involved Departments for supporting sample collection and helpful discussions.

Footnotes

  • Authors’ Contributions

    EP, CI, JF, KPM, KF, and RP carried out the molecular studies and performed the statistical analysis. EP, CI, JF, DR, SB, DD, KLB, KF, and RP participated in the design and coordination of the study and helped to draft the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    This study received no funding.

  • Received March 18, 2025.
  • Revision received March 27, 2025.
  • Accepted March 31, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Frost N,
    2. Griesinger F,
    3. Hoffmann H,
    4. Länger F,
    5. Nestle U,
    6. Schütte W,
    7. Wolf J,
    8. Reck M
    : Lung cancer in Germany. J Thorac Oncol 17(6): 742-750, 2022. DOI: 10.1016/j.jtho.2022.03.010
    OpenUrlCrossRefPubMed
  2. ↵
    1. Abdelaziz HM,
    2. Gaber M,
    3. Abd-Elwakil MM,
    4. Mabrouk MT,
    5. Elgohary MM,
    6. Kamel NM,
    7. Kabary DM,
    8. Freag MS,
    9. Samaha MW,
    10. Mortada SM,
    11. Elkhodairy KA,
    12. Fang JY,
    13. Elzoghby AO
    : Inhalable particulate drug delivery systems for lung cancer therapy: Nanoparticles, microparticles, nanocomposites and nanoaggregates. J Control Release 269: 374-392, 2018. DOI: 10.1016/j.jconrel.2017.11.036
    OpenUrlCrossRefPubMed
  3. ↵
    1. Li Y,
    2. Yan B,
    3. He S
    : Advances and challenges in the treatment of lung cancer. Biomed Pharmacother 169: 115891, 2023. DOI: 10.1016/j.biopha.2023.115891
    OpenUrlCrossRefPubMed
  4. ↵
    1. Zhu X,
    2. Yu Z,
    3. Feng L,
    4. Deng L,
    5. Fang Z,
    6. Liu Z,
    7. Li Y,
    8. Wu X,
    9. Qin L,
    10. Guo R,
    11. Zheng Y
    : Chitosan-based nanoparticle co-delivery of docetaxel and curcumin ameliorates anti-tumor chemoimmunotherapy in lung cancer. Carbohydr Polym 268: 118237, 2021. DOI: 10.1016/j.carbpol.2021.118237
    OpenUrlCrossRefPubMed
  5. ↵
    1. Farrag M,
    2. Ibrahim E,
    3. Abdelwahab H,
    4. Elsergany A,
    5. Elhadidy T
    : PDL-1 expression in lung carcinoma and its correlation with clinicopathological and prognostic characteristics. J Immunoassay Immunochem 42(6): 679-690, 2021. DOI: 10.1080/15321819.2021.1938606
    OpenUrlCrossRefPubMed
  6. ↵
    1. Pardoll DM
    : The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4): 252-264, 2012. DOI: 10.1038/nrc3239
    OpenUrlCrossRefPubMed
    1. An Q,
    2. Liu Z
    : Comparative efficacy and safety of combination therapies for advanced melanoma: a network meta-analysis. BMC Cancer 19(1): 43, 2019. DOI: 10.1186/s12885-018-5259-8
    OpenUrlCrossRefPubMed
  8. ↵
    1. Ichiki Y,
    2. Taira A,
    3. Chikaishi Y,
    4. Matsumiya H,
    5. Mori M,
    6. Kanayama M,
    7. Nabe Y,
    8. Shinohara S,
    9. Kuwata T,
    10. Takenaka M,
    11. Oka S,
    12. Hirai A,
    13. Imanishi N,
    14. Yoneda K,
    15. Kuroda K,
    16. Fujino Y,
    17. Tanaka F
    : Prognostic factors of advanced or postoperative recurrent non-small cell lung cancer targeted with immune check point inhibitors. J Thorac Dis 11(4): 1117-1123, 2019. DOI: 10.21037/jtd.2019.04.41
    OpenUrlCrossRefPubMed
  9. ↵
    1. Freeman GJ,
    2. Long AJ,
    3. Iwai Y,
    4. Bourque K,
    5. Chernova T,
    6. Nishimura H,
    7. Fitz LJ,
    8. Malenkovich N,
    9. Okazaki T,
    10. Byrne MC,
    11. Horton HF,
    12. Fouser L,
    13. Carter L,
    14. Ling V,
    15. Bowman MR,
    16. Carreno BM,
    17. Collins M,
    18. Wood CR,
    19. Honjo T
    : Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7): 1027-1034, 2000. DOI: 10.1084/jem.192.7.1027
    OpenUrlAbstract/FREE Full Text
    1. Probst HC,
    2. McCoy K,
    3. Okazaki T,
    4. Honjo T,
    5. van den Broek M
    : Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6(3): 280-286, 2005. DOI: 10.1038/ni1165
    OpenUrlCrossRefPubMed
    1. Keir ME,
    2. Liang SC,
    3. Guleria I,
    4. Latchman YE,
    5. Qipo A,
    6. Albacker LA,
    7. Koulmanda M,
    8. Freeman GJ,
    9. Sayegh MH,
    10. Sharpe AH
    : Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 203(4): 883-895, 2006. DOI: 10.1084/jem.20051776
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Tsushima F,
    2. Yao S,
    3. Shin T,
    4. Flies A,
    5. Flies S,
    6. Xu H,
    7. Tamada K,
    8. Pardoll DM,
    9. Chen L
    : Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood 110(1): 180-185, 2007. DOI: 10.1182/blood-2006-11-060087
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Dave K,
    2. Ali A,
    3. Magalhaes M
    : Increased expression of PD-1 and PD-L1 in oral lesions progressing to oral squamous cell carcinoma: a pilot study. Sci Rep 10(1): 9705, 2020. DOI: 10.1038/s41598-020-66257-6
    OpenUrlCrossRefPubMed
    1. Ishida Y,
    2. Agata Y,
    3. Shibahara K,
    4. Honjo T
    : Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11(11): 3887-3895, 1992. DOI: 10.1002/j.1460-2075.1992.tb05481.x
    OpenUrlCrossRefPubMed
    1. Sharpe AH,
    2. Pauken KE
    : The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18(3): 153-167, 2018. DOI: 10.1038/nri.2017.108
    OpenUrlCrossRefPubMed
  16. ↵
    1. Thibult ML,
    2. Mamessier E,
    3. Gertner-Dardenne J,
    4. Pastor S,
    5. Just-Landi S,
    6. Xerri L,
    7. Chetaille B,
    8. Olive D
    : PD-1 is a novel regulator of human B-cell activation. Int Immunol 25(2): 129-137, 2013. DOI: 10.1093/intimm/dxs098
    OpenUrlCrossRefPubMed
  17. ↵
    1. Kuang DM,
    2. Peng C,
    3. Zhao Q,
    4. Wu Y,
    5. Chen MS,
    6. Zheng L
    : Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 51(1): 154-164, 2010. DOI: 10.1002/hep.23291
    OpenUrlCrossRefPubMed
    1. Heeren AM,
    2. Punt S,
    3. Bleeker MC,
    4. Gaarenstroom KN,
    5. van der Velden J,
    6. Kenter GG,
    7. de Gruijl TD,
    8. Jordanova ES
    : Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix. Mod Pathol 29(7): 753-763, 2016. DOI: 10.1038/modpathol.2016.64
    OpenUrlCrossRefPubMed
  19. ↵
    1. Kim HR,
    2. Ha SJ,
    3. Hong MH,
    4. Heo SJ,
    5. Koh YW,
    6. Choi EC,
    7. Kim EK,
    8. Pyo KH,
    9. Jung I,
    10. Seo D,
    11. Choi J,
    12. Cho BC,
    13. Yoon SO
    : PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients. Sci Rep 6: 36956, 2016. DOI: 10.1038/srep36956
    OpenUrlCrossRefPubMed
  20. ↵
    1. Shinchi Y,
    2. Ishizuka S,
    3. Komohara Y,
    4. Matsubara E,
    5. Mito R,
    6. Pan C,
    7. Yoshii D,
    8. Yonemitsu K,
    9. Fujiwara Y,
    10. Ikeda K,
    11. Tamada K,
    12. Sakagami T,
    13. Suzuki M
    : The expression of PD-1 ligand 1 on macrophages and its clinical impacts and mechanisms in lung adenocarcinoma. Cancer Immunol Immunother 71(11): 2645-2661, 2022. DOI: 10.1007/s00262-022-03187-4
    OpenUrlCrossRefPubMed
  21. ↵
    1. Wagner F,
    2. Hölig U,
    3. Wilczkowski F,
    4. Plesca I,
    5. Sommer U,
    6. Wehner R,
    7. Kießler M,
    8. Jarosch A,
    9. Flecke K,
    10. Arsova M,
    11. Tunger A,
    12. Bogner A,
    13. Reißfelder C,
    14. Weitz J,
    15. Schäkel K,
    16. Troost EGC,
    17. Krause M,
    18. Folprecht G,
    19. Bornhäuser M,
    20. Bachmann MP,
    21. Aust D,
    22. Baretton G,
    23. Schmitz M
    : Neoadjuvant radiochemotherapy significantly alters the phenotype of plasmacytoid dendritic cells and 6-sulfo LacNAc(+) monocytes in rectal cancer. Front Immunol 10: 602, 2019. DOI: 10.3389/fimmu.2019.00602
    OpenUrlCrossRefPubMed
  22. ↵
    1. Wong KL,
    2. Yeap WH,
    3. Tai JJY,
    4. Ong SM,
    5. Dang TM,
    6. Wong SC
    : The three human monocyte subsets: implications for health and disease. Immunol Res 53(1-3): 41-57, 2012. DOI: 10.1007/s12026-012-8297-3
    OpenUrlCrossRefPubMed
    1. Ziegler-Heitbrock L
    : Blood monocytes and their subsets: established features and open questions. Front Immunol 6: 423, 2015. DOI: 10.3389/fimmu.2015.00423
    OpenUrlCrossRefPubMed
  24. ↵
    1. Patel AA,
    2. Zhang Y,
    3. Fullerton JN,
    4. Boelen L,
    5. Rongvaux A,
    6. Maini AA,
    7. Bigley V,
    8. Flavell RA,
    9. Gilroy DW,
    10. Asquith B,
    11. Macallan D,
    12. Yona S
    : The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med 214(7): 1913-1923, 2017. DOI: 10.1084/jem.20170355
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Boyette LB,
    2. Macedo C,
    3. Hadi K,
    4. Elinoff BD,
    5. Walters JT,
    6. Ramaswami B,
    7. Chalasani G,
    8. Taboas JM,
    9. Lakkis FG,
    10. Metes DM
    : Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One 12(4): e0176460, 2017. DOI: 10.1371/journal.pone.0176460
    OpenUrlCrossRefPubMed
  26. ↵
    1. Idel C,
    2. Loyal K,
    3. Rades D,
    4. Hakim SG,
    5. Schumacher U,
    6. Bruchhage KL,
    7. Pries R
    : Smoking-, alcohol-, and age-related alterations of blood monocyte subsets and circulating CD4/CD8 T cells in head and neck cancer. Biology (Basel) 11(5): 658, 2022. DOI: 10.3390/biology11050658
    OpenUrlCrossRefPubMed
  27. ↵
    1. Weber C,
    2. Belge KU,
    3. von Hundelshausen P,
    4. Draude G,
    5. Steppich B,
    6. Mack M,
    7. Frankenberger M,
    8. Weber KS,
    9. Ziegler-Heitbrock HW
    : Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol 67(5): 699-704, 2000. DOI: 10.1002/jlb.67.5.699
    OpenUrlCrossRefPubMed
  28. ↵
    1. Probst E,
    2. Franzen KF,
    3. Idel C,
    4. Plötze-Martin K,
    5. Fleckner J,
    6. Rades D,
    7. Bohnet S,
    8. Bruchhage KL,
    9. Pries R
    : Differential effects of anti-PD-1/PD-L1 checkpoint inhibitors on adhesion molecules and cytokine secretion by THP-1 monocytes. Anticancer Res 43(6): 2445-2454, 2023. DOI: 10.21873/anticanres.16412
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Polasky C,
    2. Steffen A,
    3. Loyal K,
    4. Lange C,
    5. Bruchhage KL,
    6. Pries R
    : Redistribution of monocyte subsets in obstructive sleep apnea syndrome patients leads to an imbalanced PD-1/PD-L1 cross-talk with CD4/CD8 T cells. J Immunol 206(1): 51-58, 2021. DOI: 10.4049/jimmunol.2001047
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Zhao Q,
    2. Bi Y,
    3. Sun H,
    4. Xiao M
    : Serum IL-5 and IFN-γ are novel predictive biomarkers for anti-PD-1 treatment in NSCLC and GC patients. Dis Markers 2021: 5526885, 2021. DOI: 10.1155/2021/5526885
    OpenUrlCrossRefPubMed
  31. ↵
    1. Moriyama Y,
    2. Horita N,
    3. Kudo M,
    4. Shinkai M,
    5. Fujita H,
    6. Yamanaka T,
    7. Ishigatsubo Y,
    8. Kaneko T
    : Monocyte nadir is a possible indicator for neutrophil nadir during lung cancer chemotherapy. Clin Respir J 11(4): 453-458, 2017. DOI: 10.1111/crj.12358
    OpenUrlCrossRefPubMed
    1. Ouyang W,
    2. Liu Y,
    3. Deng D,
    4. Zhou F,
    5. Xie C
    : The change in peripheral blood monocyte count: A predictor to make the management of chemotherapy-induced neutropenia. J Can Res Ther 14(10): 565, 2018. DOI: 10.4103/0973-1482.177502
    OpenUrlCrossRef
  33. ↵
    1. Soeda A,
    2. Morita-hoshi Y,
    3. Makiyama H,
    4. Morizane C,
    5. Ueno H,
    6. Ikeda M,
    7. Okusaka T,
    8. Yamagata S,
    9. Takahashi N,
    10. Hyodo I,
    11. Takaue Y,
    12. Heike Y
    : Regular dose of gemcitabine induces an increase in CD14+ monocytes and CD11c+ dendritic cells in patients with advanced pancreatic cancer. Jpn J Clin Oncol 39(12): 797-806, 2009. DOI: 10.1093/jjco/hyp112
    OpenUrlCrossRefPubMed
  34. ↵
    1. Cassetta L,
    2. Fragkogianni S,
    3. Sims AH,
    4. Swierczak A,
    5. Forrester LM,
    6. Zhang H,
    7. Soong DYH,
    8. Cotechini T,
    9. Anur P,
    10. Lin EY,
    11. Fidanza A,
    12. Lopez-Yrigoyen M,
    13. Millar MR,
    14. Urman A,
    15. Ai Z,
    16. Spellman PT,
    17. Hwang ES,
    18. Dixon JM,
    19. Wiechmann L,
    20. Coussens LM,
    21. Smith HO,
    22. Pollard JW
    : Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific repro-gramming, biomarkers, and therapeutic targets. Cancer Cell 35(4): 588-602.e10, 2019. DOI: 10.1016/j.ccell.2019.02.009
    OpenUrlCrossRefPubMed
  35. ↵
    1. Kiss M,
    2. Caro AA,
    3. Raes G,
    4. Laoui D
    : Systemic reprogramming of monocytes in cancer. Front Oncol 10: 1399, 2020. DOI: 10.3389/fonc.2020.01399
    OpenUrlCrossRefPubMed
  36. ↵
    1. Ingalls RR,
    2. Golenbock DT
    : CD11c/CD18, a transmembrane signaling receptor for lipopolysaccharide. J Exp Med 181(4): 1473-1479, 1995. DOI: 10.1084/jem.181.4.1473
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Postigo AA,
    2. Corbí AL,
    3. Sánchez-Madrid F,
    4. de Landázuri MO
    : Regulated expression and function of CD11c/CD18 integrin on human B lymphocytes. Relation between attachment to fibrinogen and triggering of proliferation through CD11c/CD18. J Exp Med 174(6): 1313-1322, 1991. DOI: 10.1084/jem.174.6.1313
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Dupuy AG,
    2. Caron E
    : Integrin-dependent phagocytosis – spreading from microadhesion to new concepts. J Cell Sci 121(11): 1773-1783, 2008. DOI: 10.1242/jcs.018036
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Blomberg OS,
    2. Spagnuolo L,
    3. Garner H,
    4. Voorwerk L,
    5. Isaeva OI,
    6. van Dyk E,
    7. Bakker N,
    8. Chalabi M,
    9. Klaver C,
    10. Duijst M,
    11. Kersten K,
    12. Brüggemann M,
    13. Pastoors D,
    14. Hau CS,
    15. Vrijland K,
    16. Raeven EAM,
    17. Kaldenbach D,
    18. Kos K,
    19. Afonina IS,
    20. Kaptein P,
    21. Hoes L,
    22. Theelen WSME,
    23. Baas P,
    24. Voest EE,
    25. Beyaert R,
    26. Thommen DS,
    27. Wessels LFA,
    28. de Visser KE,
    29. Kok M
    : IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer. Cancer Cell 41(1): 106-123.e10, 2023. DOI: 10.1016/j.ccell.2022.11.014
    OpenUrlCrossRefPubMed
  40. ↵
    1. Ikutani M,
    2. Yanagibashi T,
    3. Ogasawara M,
    4. Tsuneyama K,
    5. Yamamoto S,
    6. Hattori Y,
    7. Kouro T,
    8. Itakura A,
    9. Nagai Y,
    10. Takaki S,
    11. Takatsu K
    : Identification of innate IL-5–producing cells and their role in lung eosinophil regulation and antitumor immunity. J Immunol 188(2): 703-713, 2012. DOI: 10.4049/jimmunol.1101270
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Elevated PD-L1 Expression on Circulating Classical Monocytes Upon Checkpoint Inhibitor Therapy Is Associated With Increased Plasma Interleukin 5 in Patients With Lung Cancer
EVA PROBST, CHRISTIAN IDEL, JONAS FLECKNER, KIRSTIN PLÖTZE-MARTIN, DIRK RADES, SABINE BOHNET, DANIEL DRÖMANN, KARL-LUDWIG BRUCHHAGE, KLAAS FRANZEN, RALPH PRIES
Anticancer Research May 2025, 45 (5) 1915-1925; DOI: 10.21873/anticanres.17569
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords