Research ArticleExperimental Studies
Open Access

Usefulness of Biopsy Specimens for Evaluating CD103+ Tumor-resident Memory T Cells in Esophageal Cancer

SEIJI NATSUKI, YUICHIRO MIKI, HIROAKI TANAKA, MASAKI NISHIYAMA, HIROAKI KASASHIMA, TATSUNARI FUKUOKA, MAMI YOSHII, TATSURO TAMURA, MASATSUNE SHIBUTANI, TAKAHIRO TOYOKAWA, SHIGERU LEE and KIYOSHI MAEDA
Anticancer Research November 2023, 43 (11) 4823-4832; DOI: https://doi.org/10.21873/anticanres.16679

Abstract

Background/Aim: CD103+ tissue-resident memory T cells (TRM) in tumor sites are associated with a favorable prognosis and predict the effectiveness of immune checkpoint inhibitors. The detection of CD103+ TRM infiltration in biopsy samples could be beneficial for patients without surgical indications. However, the usefulness of TRM detection in biopsy tissue and the difference in TRM status between biopsy and surgical specimens’ post-neoadjuvant chemotherapy have not been elucidated. In the present study, we aimed to elucidate whether we can detect TRM in biopsy specimens and the impact of chemotherapy on TRM infiltration. Materials and Methods: Tissue sections were obtained from 46 patients with esophageal cancer who received neoadjuvant chemotherapy and underwent radical esophagectomy in 2017. Immunohistochemistry was performed using an anti-CD103 antibody for biopsy and surgical specimens. We examined the relationship between CD103 expression, clinicopathological features, and prognosis for each patient. Results: TRM infiltration was detected in the biopsy specimens. CD103 expression in biopsy specimens correlated with that in surgical specimens. Although there was no statistical significance in clinicopathological findings between CD103high and CD103low, patients with CD103high biopsy specimens exhibited favorable prognosis. The number of CD103+ cells was increased by chemotherapy: though with no survival benefit. Conclusion: Regardless of surgical indication, we were able to determine the TRM status even in biopsy specimens. CD103 evaluation at biopsy may be more useful and practical than evaluation in surgical specimens, enabling prediction of prognosis and response to immune therapy.

Key Words:

CD8+ tumor-infiltrating lymphocytes play crucial roles in antitumor immunity and reportedly provide a favorable prognosis (1-3). CD103+CD8+ tumor-infiltrating lymphocytes, called tissue-resident memory T cells (TRM), are associated with further favorable prognosis in various cancer (4-6). TRM have attracted attention for their anti-tumor function and association with the effectiveness of immune checkpoint inhibitors (ICIs). We previously investigated TRM infiltration in esophageal cancer (7). Esophageal cancer is one of the worst cancers with regard to prognosis, but we reported that TRM-rich patients exhibit a better prognosis and have fewer lymph node metastasis than TRM-poor patients (7). Additionally, the emergence of ICIs has provided more treatment options for unresectable progressive, or recurrent esophageal cancer. However, none of these patients showed a treatment effect of ICIs. Interestingly, we previously suggested that TRM in esophageal cancer is associated with the response to ICIs. Other studies have also reported that TRM has potential in the ICI treatment of gastrointestinal tumors (7, 8). The evaluation of TRM is possibly instrumental, even for ICI treatment. However, surgical specimens are required to determine the TRM status, and these specimens are typically modified by neoadjuvant chemotherapy as a standard treatment. If endoscopic biopsy specimens accurately demonstrate TRM infiltration, early prediction of patients’ prognoses and responses to ICIs in unresectable esophageal cancer might be feasible without the need for surgical specimens.

Therefore, we investigated whether we could detect TRM in biopsy specimens and correlation between TRM infiltration in biopsy and surgical specimens in order to assess the impact of neoadjuvant chemotherapy and clarify the usefulness of TRM evaluation in biopsied tissues, in patients with esophageal cancer. We also verified whether TRM infiltration in biopsy specimens could predict a favorable prognosis.

Materials and Methods

Patients and samples. This study included 87 patients with esophageal cancer who underwent radical esophagectomy at the Osaka City University (currently Osaka Metropolitan University, Osaka, Japan) in 2017. To evaluate the primary lesions and assess the changes following neoadjuvant chemotherapy, we excluded patients who (i) had undergone endoscopic treatment, including endoscopic submucosal dissection (seven patients), (ii) had undergone radiation therapy (seven patients), and (iii) had never undergone treatment before surgery (30 patients). Forty-seven patients received neoadjuvant chemotherapy and subsequently underwent radical esophagectomy. We analyzed 46 patients after excluding one patient with incomplete data. Although we obtained biopsy and surgical specimens from the included patients, six biopsy specimens had insufficient specimen data and one surgical specimen could not be evaluated because almost all the tumor tissue had disappeared after neoadjuvant chemotherapy. Thirty-nine patients were finally detected with CD103+ cells in both the specimens and were analyzed.

Chemotherapy. Indications for chemotherapy and details of the regimens were based on the esophageal cancer treatment guidelines (9). The preoperative regimens consisted of two cycles of 5-fluorouracil+cisplatin (FP), 5-fluorouracil+nedaplatin (FGP), or docetaxel+cisplatin+5-fluorouracil (DCF). The regimen schedules have been reported previously (7). FP consisted of a four-week cycle of 5-fluorouracil at 800 mg/m2 body surface area on days one through five and cisplatin at 80 mg/m2 on day one. FGP consisted of a four-week cycle of 5-fluorouracil at 800 mg/m2 on days one through five and nedaplatin at 90 mg/m2 on day one. DCF consisted of a four-week cycle of 5-fluorouracil at 800 mg/m2 on days one through five, cisplatin at 80 mg/m2 on day one, and docetaxel at 30 mg/m2 on days one and 15.

The chemotherapy dose was reduced as needed, depending on the patient’s condition and adverse events. We defined the tumor locations as upper, middle, and lower thoracic esophagus and histological type as differentiated type (well differentiated/moderately differentiated)/undifferentiated type (poorly differentiated) based on the 12th edition of the Japanese Classification of Esophageal Cancer (9). All pathological stages were recorded according to the 8th edition of the Union International Cancer Control TNM Classification (10).

Immunohistochemistry. Immunohistochemistry was performed as previously described (7). All immunostaining analyses were performed on 4-mm-thick sections of paraffin-embedded tumor blocks from biopsies and surgical specimens from patients with esophageal cancer. The sections were autoclaved for antigen retrieval using the Target Retrieval Solution [100× citrate buffer (pH 6.0); Dako, Agilent Technologies, Inc.]. Nonspecific binding was blocked using a nonspecific staining blocking reagent (prediluted; Nichirei Biosciences, Inc.). The sections were subsequently incubated at 4°C overnight with a rabbit monoclonal anti-CD103 primary antibody (clone: EPR4166; cat. no. ab1292202; 1/1,000; Abcam). The sections were then incubated with the secondary antibody for 10 min at room temperature. After washing in phosphate-buffered saline, the sections were visualized with 3-3′-diamino-benzidine for 5 min and then counterstained with hematoxylin.

Evaluation of immunohistochemistry. Tumor sections were stained with an anti-CD103 antibody and scanned at ×400 magnification. Three representative high-power fields containing CD103+ cells were randomly selected, and the average number of CD103+ cells in the three fields was calculated. The cut-off values were determined from time-dependent receiver operating characteristic (ROC) curves. The ROC curves are shown in Figure 1. The curves were based on five-year overall survival (OS). The patients were divided into two groups according to these values. All microscopy images were imported from a DP-73 digital photo filing system (Olympus).

Figure 1.
Figure 1.

Time-dependent receiver operating characteristic curves based on five-year overall survival. (a) CD103 expression in biopsy specimens. (b) CD103 expression in surgical specimens. AUC, Area under the curve; CI, confidence interval.

Ethics statement. This study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Osaka City University Ethics Committee (approval No. 3138 and 4092). Written informed consent was obtained from all patients before enrollment.

Statistical analyses. All statistical analyses were conducted using EZR, an R software package with a modified version of R Commander designed to add statistical functions frequently used in biostatistics (11). The Fisher’s exact probability test was used to compare categorical variables. The Mann-Whitney U-test was used to compare continuous variables. OS and relapse-free survival (RFS) were compared using the Kaplan-Meier method, and the significance of differences was analyzed using the log-rank test. The date of surgery was set as the starting point for OS and RFS measurements. The OS endpoint was defined as the date of death, and that of RFS was defined as the date of death or recurrence. The Cox proportional hazards model was used for the univariate prognostic analyses. Spearman’s rank correlation coefficient was used to examine correlations. p-Values <0.05 were considered to indicate statistical significance.

Results

Clinicopathological features. Forty-six patients with clinicopathological features were included in the study, as shown in Table I. The mean patient age was 65.5 years (range=42-80 years), and the group included 39 men and seven women. In addition, the group included 22 patients with Stage II disease, 21 with Stage III disease, and three with of Stage IV disease. Neoadjuvant chemotherapy regimens were used as follows: FP for 18 patients, FGP for two patients, DCF for 25 patients of DCF, and one patient received ‘other’ regimen (tegafur/gimeracil/oteracil potassium). The mean follow-up time after surgery was 59.0 months (range=1-75 months).

View this table:
Table I.

Clinicopathological features of included patients (n=46).

CD103-positive cell infiltration in biopsy and surgical specimens. Tumor sections were stained with an anti-CD103 antibody (Figure 2a). We were able to sufficiently detect CD103+ cell infiltration within the tumor sites, even in the biopsy specimens. The patients were classified into two groups based on the number of CD103+ cells infiltrating the tumor sites. According to the ROC curves, the cut-off value for biopsy specimens was determined at 11.0 cells per field, and the cut-off value for surgical specimens was determined at 10.5 cells per field. Based on these values, the patients were divided into two groups: CD103high and CD103low (Table II). There were no significant differences in age, sex, chemotherapy regimen, or pathological findings between the CD103high and CD103low groups. We examined the correlation between CD103 expression in biopsy and surgical specimens (Figure 2b). Spearman’s rank correlation coefficient indicated a significantly weak correlation between the two specimens (r=0.383, p=0.0163).

Figure 2.
Figure 2.

(a) Representative images of immunohistochemistry using an anti-CD103 antibody. Scale bar, 100 mm. (b) Correlation of CD103 expression between biopsy and surgical specimens using Spearman’s rank correlation coefficient; statistically significant, p<0.05.

View this table:
Table II.

Association between clinicopathological findings and CD103 expression in biopsy or surgical specimens.

Prognostic analyses. We analyzed the association between prognosis and CD103+ cell infiltration in biopsy and surgical specimens (Figure 3). In biopsy specimens, CD103 expression was associated with a favorable prognosis; in particular, CD103high specimens showed significantly prolonged OS (Figure 3a; p=0.040 for OS, p=0.050 for RFS). In the present study, there were no statistically significant differences in survival between the CD103high and CD103low groups, but a favorable survival trend was observed (Figure 3b; p=0.121 for OS). Considering the poor prognosis of esophageal cancer, we examined the short- and mid-term prognoses of the two specimens (Table III). Favorable prognostic trends were observed for CD103 expression in both groups. In particular, CD103-high biopsy specimens were associated with good OS [hazard ratio (HR)=0.253, p=0.018 for 3-year OS, and HR=0.364 p=0.049 for 5-year OS] and 3-year RFS (HR=0.348, p=0.033).

Figure 3.
Figure 3.

Kaplan-Meyer plots of prognostic comparison between CD103high and CD103low. Overall survival and relapse-free survival were compared by the log-rank test; statistically significant, p<0.05, in biopsy specimens (a) and surgical specimens (b).

View this table:
Table III.

Analyses for prognostic factors.

Comparison of CD103 expression between biopsy and surgical specimens. We examined the change in CD103 expression between biopsy and surgical specimens of each patient. CD103 expression was higher in surgical specimens than in biopsy specimens (Figure 4a; p=0.0279). We divided the patients into two groups based on the change in CD103+ cell detection between the biopsy and surgical specimens: TRM-decreased and TRM-increased (Figure 4b,c). CD103-decreased samples showed a significant decrease in CD103 expression from biopsy to surgical specimens (Figure 4b; p=0.0076). In contrast, the other samples showed significant increase in CD103 expression (Figure 4c; p<0.0001). We examined whether an increase or decrease in CD103+ cell would offer a prognostic effect; however, there were no significant difference in OS and RFS (Figure 4d; p=0.378 and 0.553, respectively). Further, we focused on the change in CD103 status from biopsy to surgical specimens. Among the patients categorized as CD103high on biopsy, the number of CD103+ cells did not significantly differ between biopsy and surgical specimens (Figure 4e; p=0.375). On the other hand, for patients categorized as CD103low on biopsy, the number of CD103+ cells was significantly higher in surgical specimens than in biopsy specimens (Figure 4f; p=0.0046). We compared the prognosis separately for each CD103 status change (Figure 4g; Biopsy to Surgical specimens, low-low/low-high/high-low/high-high). Low-low patients exhibited worse prognoses and low-high patients tended to show relatively better prognoses than low-low patients, although the differences were not statistically significant. Regarding the analysis of patients with CD103high at biopsy, there were no differences between CD103 high and low in surgical specimens (high-high and high-low). Finally, we examined the relationship between changes in CD103 expression with the chemotherapy regimen and the histological effect grade, but there were no significant differences (Table IV).

Figure 4.
Figure 4.
Figure 4.

(a-c) Summarized dot plots of CD103 expression analysis between biopsy and surgical specimens using the Mann Whitney U-test; statistically significant, p<0.05. (a) All evaluable specimens; (b) CD103-decreased samples from biopsy to surgical specimens; (c) CD103-increased samples from biopsy to surgical specimens (d) Kaplan-Meyer plots of prognostic comparison using log-rank test; statistically significant, p<0.05. Comparison of change in the number of CD103+ cells between biopsy and surgical specimens; (e, f) Summarized dot plots of CD103 expression analysis between biopsy and surgical specimens using the Mann Whitney U-test; statistically significant, p<0.05; (e) CD103high in biopsy specimens; (f) CD103low in biopsy specimens; (g) Kaplan-Meyer plots of prognostic comparison using the log-rank test; statistically significant, p<0.05. We compared prognosis with each change of CD103 status between biopsy and surgical specimens.

View this table:
Table IV.

Association CD103 expression and status after chemotherapy.

Discussion

Biopsy tissues are relatively small and superficial samples compared to surgical specimens. Therefore, it was necessary to clarify whether we can detect TRM in biopsy specimens. We also needed to elucidate the difference in TRM infiltration between biopsy and surgical specimens and verify whether TRM in biopsy samples was associated with a favorable prognosis. In this study, we demonstrated that biopsy specimens obtained before initiating treatment for esophageal cancer are valuable for evaluating TRM infiltration into tumor sites. We were able to sufficiently detect TRM cell infiltration even in a few biopsy specimens. TRM-rich biopsy specimens are also associated with favorable prognosis. Our results suggest that accurate detection of TRM status from biopsy specimens can facilitate the prediction of prognosis and treatment decisions.

Esophageal cancer is one of the worst cancers regarding prognosis and numerous studies have been conducted in order to find independent prognostic factors and anti-tumor molecules (12, 13). We then focused on TRM. Tumor-infiltrating lymphocytes expressing CD103, primarily CD103+CD8+ T cells, referred to as TRM, are long-lived memory T cells with significant cytotoxicity (14). We also reported the favorable prognostic impacts, in terms of antitumor immunity, and survival advantages, of TRM infiltration in gastric and esophageal cancers (6, 7); however, since not all patients undergo surgery, surgical specimens for evaluating TRM status are not always obtained. Biopsy specimens are usually obtained to confirm diagnosis and determine treatment strategies; therefore, a biopsy may become even more informative. In addition to providing survival benefit, TRM could potentially predict the response to ICIs (6, 7, 15). Since ICIs have been considered treatment options for unresectable progressive esophageal cancer, determining the TRM status of patients without surgical indications becomes necessary. This study likely highlights the usefulness of biopsy in guiding decisions regarding subsequent immune therapy. However, since none of the patients in this study received ICIs, it was not possible to establish a relationship between CD103 expression on biopsy and the response to ICIs.

In Japan, surgery with or without neoadjuvant chemotherapy is the standard-of-care in patients with resectable esophageal cancer (clinical Stage I to III) in accordance with the esophageal cancer practice guidelines (9). Patients with clinical Stage I esophageal cancer first undergo surgery without neoadjuvant chemotherapy, whereas those with clinical Stage II or Stage III esophageal cancer receive neoadjuvant chemotherapy prior to surgery. Patients without neoadjuvant chemotherapy were presumed to maintain the same TRM status between biopsy and surgical specimens if TRM was detected in the biopsy. Consequently, this study included patients who received neoadjuvant chemotherapy to evaluate changes and discrepancies in TRM status between biopsy and surgical specimens. Our study demonstrated a correlation between CD103 expression in biopsy and surgical specimens. CD103 expression in biopsies is associated with a favorable prognosis. Although CD103 expression in surgical specimens was associated with favorable survival trends, this association did not reach statistical significance. We explored why CD103 expression in biopsy specimens was a more significant prognostic indicator compared to surgical specimens. In a previous study, we reported that TRM in chemotherapy-experienced patients exhibited improved survival compared to chemotherapy-naïve patients (7). Therefore, we focused on assessing the levels of CD103 expression and CD103 status in both biopsy and surgical specimens. Following neoadjuvant chemotherapy, many patients showed increased CD103 expression within tumors. This result is consistent with previous reports suggesting that chemotherapy induces cytotoxic T cell infiltration similar to TRM involvement in immunogenic cell death (16, 17). There were samples in which CD103+ cell counts decreased. We compared prognoses between samples with decreased and increased CD103+ cells after chemotherapy. However, there were no significant differences between groups. Subsequently, we compared changes in CD103 status after chemotherapy. The group with CD103low on biopsy showed an increase in CD103 expression after chemotherapy, but they may have a lower survival benefit compared to the group with CD103high on biopsy. In contrast, patients with CD103high on biopsy, whether surgical specimens were CD103high or low, showed no statistically significant difference in survival. It is possible that CD103+ cells could not be sufficiently detected and counted because of tumor shrinkage caused by chemotherapy. It has recently clarified the effectiveness of neoadjuvant chemotherapy including docetaxel (18, 19) and we previously indicated the association between docetaxel regimen and TRM infiltration (7): however, no statistically significant differences in the chemotherapy regimens and histological responses were observed because of small sample sizes in the present study. Because neoadjuvant chemotherapy cause changes in the tumor immune environment, CD103 evaluation at biopsy may be more useful and practical than using surgical specimens.

TRM have specific surface markers, such as CD103, CD69, CD49a, and CD44 (20-23). However, CD103 expression is important for the detection of TRM that infiltrate tumor sites and is associated with strong cytotoxicity (7, 21). In addition, CD103 can be expressed not only on TRM but also on regulatory T cells and dendritic cells (24, 25); however, we previously clarified that most CD103+ cells that infiltrate into tumor sites were TRM (7). Thus, evaluating CD103 expression at tumor sites is considered reasonable for analyzing tumor infiltrating TRM.

The present study had several limitations. First, it was a retrospective study with a small sample size. Second, this study primarily used immunohistochemistry; therefore, we could not demonstrate a difference in TRM infiltration between biopsy and surgical specimens. Therefore, further prospective studies with larger sample sizes are warranted.

Conclusion

In conclusion, CD103+ cells were detectable in biopsy specimens before surgery, and CD103+ cell infiltration in biopsy specimens was correlated with infiltration in surgical specimens. Patients with CD103high in biopsy also exhibited favorable prognoses. We can determine the TRM status even from biopsy specimens, which may enable us to predict the prognosis and response to immune therapy.

Footnotes

  • Authors’ Contributions

    SN acquired, analyzed, and interpreted the data, and drafted the manuscript. YM and HT contributed substantially to the study conception and design, interpreted the data, and critically revised the manuscript. MN, HK, TF, MY, TTa, MS, TTo, and SL acquired and analyzed the data. KM contributed to the study conception and design and critically revised the manuscript. All the Authors have read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received August 9, 2023.
  • Revision received September 7, 2023.
  • Accepted September 11, 2023.

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).

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Usefulness of Biopsy Specimens for Evaluating CD103+ Tumor-resident Memory T Cells in Esophageal Cancer
SEIJI NATSUKI, YUICHIRO MIKI, HIROAKI TANAKA, MASAKI NISHIYAMA, HIROAKI KASASHIMA, TATSUNARI FUKUOKA, MAMI YOSHII, TATSURO TAMURA, MASATSUNE SHIBUTANI, TAKAHIRO TOYOKAWA, SHIGERU LEE, KIYOSHI MAEDA
Anticancer Research Nov 2023, 43 (11) 4823-4832; DOI: 10.21873/anticanres.16679
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