Abstract
Background/Aim: Immune checkpoint inhibitors have demonstrated significant clinical efficacy in patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. Although current evidence is based on studies with limited sample sizes, recent findings suggest that anti–programmed cell death-1 (PD-1) antibodies are highly effective in patients with locally advanced dMMR/MSI-H rectal cancer.
Case Report: We report the case of a 70-year-old man with locally advanced MSI-H rectal cancer who exhibited a remarkable and durable response to pembrolizumab. Histopathological examination revealed the infiltration of CD8-positive T lymphocytes and clusters of PD-L1–expressing macrophages within the tumor tissue. CD103-positive tissue-resident memory T-cells have also been identified in the tumor microenvironment, suggesting a robust and sustained local immune response.
Conclusion: Immune checkpoint blockade may represent a promising nonsurgical treatment option for patients with locally advanced dMMR/MSI-H rectal cancer.
- Rectal cancer
- mismatch repair-deficient
- microsatellite instability-high
- pembrolizumab
- tissue-resident memory T cells
Introduction
According to real-world data, microsatellite instability-high (MSI-H) status has been reported in approximately 4% of Japanese patients with unresectable advanced colorectal cancer in the Japanese population (1). Pembrolizumab, an anti–programmed cell death-1 (PD-1) antibody, has demonstrated significant clinical benefits, with a favorable safety profile for mismatch repair-deficient (dMMR)/ MSI-H metastatic colorectal cancer (2, 3). Recent studies demonstrated the striking efficacy of anti-PD-1 antibodies in patients with locally advanced dMMR/MSI-H rectal cancer (4-6). However, the number of reported cases remains small, and the available clinical data remain limited. Here, we report a case of locally advanced MSI-H rectal cancer that exhibited a remarkable therapeutic response to pembrolizumab, resulting in substantial shrinkage of primary rectal tumor. The patient achieved durable disease control and remained progression-free for more than 1 year following the discontinuation of pembrolizumab. In addition, we performed a pathological investigation to explore the potential mechanisms underlying the effectiveness of immune checkpoint blockade.
Case Report
A 70-year-old man presented with a 1-month history of defecation difficulty. Colonoscopy revealed a tumorous lesion in the rectum (Figure 1A) and histopathological examination of the biopsy specimen confirmed a poorly differentiated adenocarcinoma. Computed tomography (CT) demonstrated tumor invasion into the surrounding tissues (Figure 1B) and multiple metastatic pelvic lymph nodes (Figure 1B). The patient was diagnosed as having locally advanced rectal cancer with lymph node metastases. Although surgical resection was considered, the patient had severe pulmonary emphysema, and the risk of respiratory complications under general anesthesia was deemed high. Therefore, curative surgery was considered unfeasible. Molecular testing of the primary lesion revealed wild-type RAS, BRAF and high microsatellite instability (MSI-H). Based on this finding, we treated the patient with pembrolizumab (200 mg on day 1 every 3 weeks). After eight cycles of pembrolizumab monotherapy, follow-up colonoscopy revealed complete clinical regression of the primary rectal tumor, leaving behind a scar (Figure 1C), and the biopsy specimen from the same site showed no evidence of a tumor. CT demonstrated a marked reduction in the size of the primary rectal tumor (Figure 1D) and the previously enlarged pelvic lymph nodes became undetectable (Figure 1D). Mild skin toxicity was observed, and no severe adverse events were observed. The patient had severe comorbid pulmonary emphysema and was concerned about the potential adverse events associated with pembrolizumab. Therefore, the patient declined to continue treatment with pembrolizumab. The patient remains under observation and has been progression-free for more than 1 year after treatment discontinuation.
Clinical examinations. (A) Initial colonoscopy revealed a bulky tumorous lesion in the rectum. (B) CT demonstrated direct extension of the rectal tumor into adjacent structures, consistent with locally advanced disease, along with multiple metastatic pelvic lymph nodes. (C) Follow-up colonoscopy revealed complete regression of the primary rectal tumor, with only a residual scar visible. (D) Contrast-enhanced CT after treatment demonstrated marked shrinkage of the primary lesion, and the previously enlarged pelvic lymph nodes were no longer detectable. CT: Computed tomography.
Additional pathological examinations. We retrospectively analyzed a biopsy specimen of primary rectal cancer for pathological research. Hematoxylin and eosin (H&E) staining revealed a poorly differentiated adenocarcinoma with prominent infiltration of immune cells, predominantly lymphocytes (Figure 2A). Cancer cells were positive for MLH1, MSH2, and PMS2, but negative for MSH6 (Figure 2B), indicating that the cancer cell were dMMR.
Pathological observations. (A) Hematoxylin and Eosin staining of the biopsy specimen was presented. Poorly differentiated adenocarcinoma with increased infiltration of immune cells was observed. (B) IHCs of mismatch repair-related proteins were done. Immune cells were positive for all factors. IHC: Immunohistochemistry.
Immunohistochemistry (IHC) for PD-L1, HLAs, and immune cells was also performed on the biopsy specimens. PD-L1 positive in stromal cells seemed to be infiltrating the macrophages. The cancer cells expressed high levels of HLA-A/B/C (Figure 3A). HLA-DR was negative of weakly positive in cancer cells, whereas stromal cells expressed higher levels of HLA-DR (Figure 3A). High numbers of CD66b-positive neutrophils and Iba1-positive macrophages infiltrated cancer nests (Figure 3B). Although the density was lower than that of myeloid cells, such as neutrophils and macrophages, many CD3−, CD8−, and CD103-positive cells were also detected in the cancer nests (Figure 3C).
Additional IHC analysis. (A) IHC of PD-L1, HLA-A/B/C (class I), and HLA-DR (class II) were performed. (B) IHC of CD66b (neutrophil) and Iba1 (macrophage) were presented. (C) The IHC of three lymphocyte markers are presented. CD3, Marker of pan-T-lymphocytes; CD8, marker of cytotoxic T-lymphocytes; CD103, marker for TRM cells. (D) Multiplex IHC of CD3, CD8, and CD103. IHC: Immunohistochemistry.
Multiplex IHC was performed to analyze the detailed subpopulations of infiltrating lymphocytes. Half of the CD3-positive lymphocytes tested positive for CD103. 30% of the CD8-positive lymphocytes and 70% of CD3-positive and CD8-negative (considered as CD4-positive lymphocytes) cells were CD103-positive tissue resident memory T cells (TRM) (Figure 3D).
Discussion
In this case report, we present a case of locally advanced dMMR/MSI-H rectal cancer that showed a remarkable response to pembrolizumab monotherapy. The clinical benefit of pembrolizumab in dMMR/MSI-H metastatic colorectal cancer was previously demonstrated in a phase III KEYNOTE-177 trial (2, 3). Pembrolizumab has demonstrated durable antitumor activity as a first-line treatment for dMMR/MSI-H metastatic colorectal cancer, with an overall response rate (ORR) of 45% and a complete response (CR) rate of 13% (3), and pembrolizumab monotherapy represents a viable treatment option for patients with previously untreated metastatic colorectal cancer.
Recent studies have highlighted the remarkable efficacy of anti-PD-1 antibodies in patients with locally advanced dMMR/MSI-H rectal cancer (4-6). In a phase II trial investigating dostarlimab, the administration of eight cycles at 3-week intervals led to a clinical complete response (cCR) in all 49 patients with locally advanced dMMR rectal cancer who completed the treatment protocol (4). Similarly, a phase II trial of neoadjuvant anti–PD-1 therapy using sintilimab reported a CR rate of 75%, including three pathological complete responses (pCR) and nine cCRs among 16 patients (5). Furthermore, a retrospective analysis of sintilimab, tislelizumab, and pembrolizumab as neoadjuvant anti–PD-1 therapies demonstrated a CR rate of 90% in 20 patients with locally advanced rectal cancer, with 11 achieving pCR and 7 achieving cCR or near-cCR (6). Although limited by the small patient numbers, these results indicate that such strategies could potentially serve as organ-preserving alternatives to conventional surgical treatments.
The combination of nivolumab and ipilimumab demonstrated clinically significant efficacy in patients with dMMR/MSI-H metastatic colorectal cancer in the phase III CheckMate 8HW trial (7, 8). Compared to nivolumab monotherapy, the combination therapy resulted in a significantly longer progression-free survival and a higher overall response rate. Although only 57% of the patients had not received prior systemic therapy, the combination of nivolumab and ipilimumab achieved an ORR of 71%, including a CR rate of 30% (8). In patients with locally advanced dMMR colon cancer, neoadjuvant therapy with nivolumab and ipilimumab, administered as two doses of nivolumab (on days 1 and 15) and a single dose of ipilimumab (on day 1), produced a major pathological response rate of 95% (with ≤10% residual viable tumor) and a pCR rate of 68% (9).
In the treatment of rectal cancer, non-surgical strategies include chemoradiotherapy (CRT). Inflammatory markers such as the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio have been reported to be associated with prognosis in patients with MSI-H rectal cancer (10). In addition, the CD155/T cell immunoreceptor with Ig and ITIM domains (TIGIT) axis has been implicated in the tumor immune microenvironment, with CD155 expression reported to be associated with therapeutic response to CRT in rectal cancer (11). Although our patient did not receive CRT, these findings suggest that both systemic immune-inflammatory status and local immune checkpoint pathways may influence treatment outcomes in rectal cancer.
Pathological analysis revealed prominent infiltration of immune cells, predominantly lymphocytes, including CD8-positive T cells and clusters of PD-L1–expressing macrophages. PD-L1–expressing macrophages are known to bind to PD-1 on T cells, thereby suppressing antitumor immune activity (12). Thus, pembrolizumab administration likely inhibited PD-1/PD-L1 interaction, restored T-cell function, and contributed to the observed antitumor effects. Furthermore, the pathological findings suggested a role for CD8+ tissue-resident memory T (TRM) cells. These cells do not circulate in the peripheral blood but persist long-term within the tumor microenvironment (13). CD8+ TRM cells have been implicated in robust antitumor immune responses. They are phenotypically characterized by expression of CD103 [αE(CD103)β7] and/or CD49a [α1(CD49a)β1] integrins, along with CD69. Notably, CD8+ TRM cells have also been identified as favorable prognostic markers across various cancer types and promising predictive biomarkers for the clinical efficacy of immune checkpoint inhibitor (ICI) therapies (14). In gastrointestinal cancers, TRM cells have been reported to function not only as indicators of patient prognosis but also as predictive biomarkers of therapeutic responsiveness to ICIs (15). The infiltration of CD103+ cells within tumor tissue specimens has been associated with favorable survival outcomes in patients with recurrent esophageal cancer treated with nivolumab therapy (16). Furthermore, high frequency of CD103 expression in peripheral blood T cells has been reported as a potential predictive biomarker for the therapeutic efficacy of anti-PD-1 treatment in patients with advanced gastric cancer (17). MSI-H colorectal cancers have been reported to harbor a higher proportion of CD8-positive TRM cells (18). Therefore, pembrolizumab may have further enhanced antitumor immunity by activating TRM cells.
Conclusion
We reported a case of locally advanced MSI-H rectal cancer that exhibited a remarkable response to pembrolizumab treatment. Histopathological analysis demonstrated infiltration of CD103-positive TRM cells and clusters of PD-L1–expressing macrophages within the tumor, suggesting the restoration of antitumor immunity through immune checkpoint blockade. The presence of TRM cells may indicate their potential contribution to therapeutic efficacy.
Acknowledgements
We would like to thank Editage (www.editage.jp) for English language editing.
Footnotes
Authors’ Contributions
Conceptualization: Ayumu Hosokawa. Contributions to patient care: Ayumu Hosokawa, Yukiko Otsuki, Hotaka Tamura, and Akiko Ichihara. Pathological and immunohistochemical analyses: Tsuyoshi Fukushima, Rin Yamada, and Yoshihiro Komohara. Writing the original draft: Ayumu Hosokawa. Writing, review, and editing: Yoshihiro Komohara. All Authors read and approved the final manuscript.
Conflicts of Interest
None of the Authors has any conflicts of interest to declare in relation to this study.
Artificial Intelligence (AI) Disclosure
During the preparation of this manuscript, a large language model (ChatGPT, OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning–based image enhancement tools.
- Received July 28, 2025.
- Revision received August 20, 2025.
- Accepted August 26, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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