Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment

Sep 24, 2026

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Background: Small bowel adenocarcinoma (SBA) shows distinct genomic profiles from gastric and colorectal cancers, making SBA-specific chemotherapy important. PD-L1 and PD-L2 expression in SBA remains incompletely characterized, and anti-PD-L1/PD-1 efficacy may depend on tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME), including the FoxP3+ to CD8+ ratio. Aim: Determine the clinicopathological significance of PD-L1/2 expression by TIL status. Methods: Immunohistochemistry assessed PD-L1, PD-L2, CD8, FoxP3, and mismatch repair proteins in 50 primary SBA cases. Kaplan–Meier and Cox analyses evaluated survival associations. Results: PD-L1/PD-L2 CPS and TIL-related markers correlated with mismatch repair deficiency, invasion depth, histological differentiation, and cancer-specific survival. Conclusion: PD-L1/2 significance varies by TME status; checkpoint inhibitors may benefit patients with low FoxP3/CD8 and PD-L2 expression.

LanguageEnglish

CategoryHealthcare

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Pages17

Reading Time43 min

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| W | J | G | World Journal of
Gastroenterology | | --- | --- | --- | --- | Submit a Manuscript: [https://www.f6publishing.com](https://www.f6publishing.com) World J Gastroenterol 2023 October 28; 29(40): 5566-5581 DOI: 10.3748/wjg.v29.i40.5566 ISSN 1007-9327 (print) ISSN 2219-2840 (online) ORIGINAL ARTICLE Retrospective Study Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment Aitoshi Hoshimoto, Atsushi Tatsuguchi, Ryohei Hamakubo, Takayoshi Nishimoto, Jun Omori, Naohiko Akimoto, Shu Tanaka, Shunji Fujimori, Tsutomu Hatori, Akira Shimizu, Katsuhiko Iwakiri Specialty type: Gastroenterology and hepatology Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): B, B Grade C (Good): C Grade D (Fair): 0 Grade E (Poor): 0 P-Reviewer: Qin J, China; Zhe MM, China; Tsoulfas G, Greece Received: August 14, 2023 Peer-review started: August 14, 2023 First decision: September 19, 2023 Revised: October 4, 2023 Accepted: October 23, 2023 Article in press: October 23, 2023 Published online: October 28, 2023 Aitoshi Hoshimoto, Atsushi Tatsuguchi, Ryohei Hamakubo, Takayoshi Nishimoto, Jun Omori, Naohiko Akimoto, Shu Tanaka, Shunji Fujimori, Katsuhiko Iwakiri, Department of Gastroenterology, Nippon Medical School, Tokyo 113-8603, Japan Aitoshi Hoshimoto, Atsushi Tatsuguchi, Akira Shimizu, Department of Analytic Human Pathology, Nippon Medical School, Tokyo 113-8603, Japan Tsutomu Hatori, Department of Pathology, Nippon Medical School, Chiba Hokusoh Hospital, Chiba 270-1694, Japan Corresponding author: Atsushi Tatsuguchi, MD, PhD, Associate Professor, Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. [tachan@nms.ac.jp](tachan@nms.ac.jp) Abstract BACKGROUND Comprehensive genomic analysis has shown that small bowel adenocarcinoma (SBA) has different genomic profiles from gastric and colorectal cancers. Hence, it is essential to establish chemotherapeutic regimens based on SBA characteristics. The expression of programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2) in SBA is not fully understood. Anti-PD-L1/PD-1 therapy uses tumor-infiltrating lymphocytes (TILs); therefore, the status of TILs in the tumor microenvironment (TME) may influence their efficacy. The ratio of FoxP3+ to CD8+ T cells has been reported to be useful in predicting the prognosis of digestive system cancers. AIM To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues. METHODS We performed immunohistochemical analysis for PD-L1, PD-L2, CD8, FoxP3, and DNA mismatch repair (MMR) proteins using formalin-fixed, paraffin-embedded tissues from 50 patients diagnosed with primary SBA. The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infilt- WJG [https://www.wjgnet.com](https://www.wjgnet.com) 5566 October 28, 2023 Volume 29 Issue 40 Hoshimoto A et al. PD-L1/2 expression in small bowel adenocarcinoma rating immune cells throughout the tumor center and invasive margins, and finally evaluated using the combined positive score (CPS) . We assessed CD8+ and FoxP3+ T cells in the intratumoral and tumor-surrounding stroma. Subsequently, we calculated and summed the ratio of FoxP3 to CD8+ T cell counts. Immune-related cell densities were graded as low or high. Immunohistochemical results were compared with clinicopathological factors and patient prognosis. The distribution of cancer-specific survival (CSS) was estimated using the Kaplan–Meier method, and the log-rank test was used to test for significant differences in CSS. A Cox proportional hazard model was also used to assess the effect of

FAQs

What was the study designed to evaluate in small bowel adenocarcinoma?

It evaluated the clinicopathological significance of PD-L1/PD-L2 expression according to the status of tumor-infiltrating lymphocytes in SBA tissues.

How were PD-L1, PD-L2, and immune markers measured?

The study used immunohistochemical analysis for PD-L1, PD-L2, CD8, FoxP3, and DNA mismatch repair proteins on formalin-fixed, paraffin-embedded tissue from 50 primary SBA patients.

Which immune and PD-L2 findings were associated with patient prognosis?

Higher I-PD-L1 and I-PD-L2 levels were associated with better cancer-specific survival overall, while patients with PD-L2 CPS ≥ 10 tended to have worse prognosis in the FoxP3/CD8-low subgroup.

Sep 24, 2026

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