Retrospective Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2023; 29(40): 5566-5581
Published online Oct 28, 2023. doi: 10.3748/wjg.v29.i40.5566
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
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
Author contributions: Hoshimoto A designed and performed the research and wrote the paper; Tatsuguchi A designed the research and contributed to the analysis; Hamakubo R, Nishimoto T, Omori J, Akimoto N, Tanaka S, Fujimori S, and Hatori T provided clinical advice; Shimizu A and Iwakiri K supervised the report; All authors have read and approve the final manuscript.
Institutional review board statement: The study was reviewed and approved by the Nippon Medical School Institutional Review Board (Approval No. B-2020-164).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Atsushi Tatsuguchi, MD, PhD, Associate Professor, Department of Gastroenterology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
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

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.


To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues.


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-infiltrating 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 tumor variables on CSS.


PD-L1 expression was positive in 34% in tumor cells (T-PD-L1) and 54% in tumor-infiltrating immune cells (I-PD-L1) of the cases examined. T-PD-L2 was positive in 34% and I-PD-L2 was positive in 42% of the cases. PD-L1 CPS ≥ 10 and PD-L2 CPS ≥ 10 were observed in 50% and 56% of the cases, respectively. Deficient MMR (dMMR) was 14% of the cases. T-PD-L1, I-PD-L1 and PD-L1 CPS ≥ 10 were all significantly associated with dMMR (P = 0.037, P = 0.009, and P = 0.005, respectively). T-PD-L1, I-PD-L1, and PD-L1 CPS ≥ 10 were all associated with deeper depth of invasion (P = 0.001, P = 0.024, and P = 0.002, respectively). I-PD-L2 expression and PD-L2 CPS ≥ 10 were significantly higher in the differentiated histological type (P = 0.015 and P = 0.030, respectively). The I-PD-L1 and I-PD-L2 levels were significantly associated with better CSS (P = 0.037 and P = 0.015, respectively). CD8-high was significantly associated with less lymph node metastasis (P = 0.047), less distant metastasis (P = 0.024), less peritoneal dissemination (P = 0.034), and earlier TNM stage (P = 0.047). The CD8-high group had better prognosis than the CD8-low group (P = 0.018). FoxP3 expression was not associated with any clinicopathological factors or prognosis. We found that patients with PD-L2 CPS ≥ 10 tended to have worse prognosis in the FoxP3/CD8-low group (P = 0.088).


The clinicopathological significance of PD-L1/2 expression may differ depending on the TME status. Immune checkpoint inhibitors may improve the prognosis of SBA patients with low FoxP3/CD8 ratio and PD-L2 expression.

Keywords: Small bowel adenocarcinoma, Programmed cell death-ligand 1, Programmed cell death-ligand 2, Tumor microenvironment, Tumor-infiltrating lymphocytes, Regulatory T-cells

Core Tip: We investigated the clinicopathological significance of programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2) expression in association with the infiltration of FoxP3+ and CD8+ T cells into the tumor microenvironment (TME) to identify PD-L/PD-1 immunotherapy candidates among patients with small bowel adenocarcinoma (SBA). We demonstrated that the status of the TME affects the clinical significance of PD-L1 and PD-L2. PD-L2 may be associated with poor prognosis of SBA patients with a high immune cell infiltration.