PMID- 36860286 OWN - NLM STAT- MEDLINE DCOM- 20230727 LR - 20230727 IS - 2767-9764 (Electronic) IS - 2767-9764 (Linking) VI - 1 IP - 2 DP - 2021 Nov TI - Dipeptidyl Peptidase (DPP)-4 Inhibitor Impairs the Outcomes of Patients with Type 2 Diabetes Mellitus After Curative Resection for Colorectal Cancer. PG - 106-114 LID - 10.1158/2767-9764.CRC-21-0042 [doi] AB - Dipeptidyl peptidase IV inhibitor (DPP-4i) has been shown to act either as a promoter or as a suppressor for cancer. Although epidemiologic studies suggest that DPP-4i does not correlate with the development of malignancies, its effects on cancer metastases are controversial. We evaluated the impact of DPP-4i on postoperative outcomes of the diabetic patients with colorectal cancer and microscopic features of the resected tumors. In 260 consecutive patients with type 2 diabetes mellitus (T2DM) who underwent curative resection of colorectal cancer, the correlation between DPP-4i use and prognosis was retrospectively examined. Expression of Zeb1 on tumor cells and density of infiltrating immune cells were quantitatively evaluated with multicolor IHC in 40 tumors from DPP-4i users, 40 tumors from propensity score-matched users, and 40 tumors from nonusers. Postoperative disease-free survival (DFS) was significantly lower in 135 patients treated with DPP-4i compared with 125 nontreated patients [5-year DFS, 73.7% vs. 87.4%; HR, 1.98; 95% confidence interval (CI), 1.05-3.71; P = 0.035]. IHC revealed that the number of Zeb1(+) tumor cells increased in tumors from DPP-4i-treated patients than tumors from nonusers (P < 0.01). The densities of CD3(+) and CD8(+) T cells were significantly lower in tumors from DPP-4i users (P < 0.01) with decreased density of tertiary lymphoid structures (P < 0.001). However, the density of M2-type tumor-associated macrophages with CD68(+) CD163(+) phenotypes was significantly higher (P < 0.01) in tumors from DPP-4i users. Exposure of colorectal cancer to DPP-4i may accelerate epithelial-to-mesenchymal transition (EMT) creating a tumor-permissive immune microenvironment, which might impair the outcomes of the patients with colorectal cancer and T2DM. SIGNIFICANCE: DPP-4i has been shown to enhance the antitumor effects of immunotherapy. However, we found that DPP-4i significantly impairs the outcomes of patients with colorectal cancer who underwent curative resection, possibly through acceleration of EMT and creation of a tumor-permissive immune microenvironment. This suggests that DPP-4i must be used with caution until its safety is fully confirmed by further studies of the mechanistic effects on existing cancers in humans. CI - (c) 2021 The Authors; Published by the American Association for Cancer Research. FAU - Saito, Akira AU - Saito A AD - Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Kitayama, Joji AU - Kitayama J AD - Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Horie, Hisanaga AU - Horie H AD - Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Koinuma, Koji AU - Koinuma K AD - Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Kawashima, Rie AU - Kawashima R AD - Department of Oral and Maxillofacial Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Ohzawa, Hideyuki AU - Ohzawa H AD - Departments of Clinical Oncology and Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Yamaguchi, Hironori AU - Yamaguchi H AD - Departments of Clinical Oncology and Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Kawahira, Hiroshi AU - Kawahira H AD - Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Mimura, Toshiki AU - Mimura T AD - Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Lefor, Alan Kawarai AU - Lefor AK AUID- ORCID: 0000-0001-6673-5630 AD - Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. FAU - Sata, Naohiro AU - Sata N AD - Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211122 PL - United States TA - Cancer Res Commun JT - Cancer research communications JID - 9918281580506676 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - EC 3.4.14.- (Dipeptidyl-Peptidases and Tripeptidyl-Peptidases) MH - Humans MH - *Diabetes Mellitus, Type 2/complications MH - *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use MH - Retrospective Studies MH - CD8-Positive T-Lymphocytes MH - Hypoglycemic Agents/adverse effects MH - Dipeptidyl-Peptidases and Tripeptidyl-Peptidases MH - *Colorectal Neoplasms/drug therapy MH - Tumor Microenvironment PMC - PMC9973397 COIS- H. Yamaguchi reports grants from Taiho Pharmaceutical, Co., Ltd, Nippon Kayaku Co., Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., and grants from ONO Pharmaceutical Co., Ltd. outside the submitted work. No other disclosures were reported. EDAT- 2021/11/22 00:00 MHDA- 2021/11/22 00:01 PMCR- 2021/11/22 CRDT- 2023/03/02 02:05 PHST- 2021/08/25 00:00 [received] PHST- 2021/11/01 00:00 [revised] PHST- 2021/11/11 00:00 [accepted] PHST- 2023/03/02 02:05 [entrez] PHST- 2021/11/22 00:00 [pubmed] PHST- 2021/11/22 00:01 [medline] PHST- 2021/11/22 00:00 [pmc-release] AID - CRC-21-0042 [pii] AID - 10.1158/2767-9764.CRC-21-0042 [doi] PST - epublish SO - Cancer Res Commun. 2021 Nov 22;1(2):106-114. doi: 10.1158/2767-9764.CRC-21-0042. eCollection 2021 Nov.