TIM-3 Expression and M2 Polarization of Macrophages in the TGFβ-Activated Tumor Microenvironment in Colorectal Cancer

Author:

Katagata Masanori1,Okayama Hirokazu1ORCID,Nakajima Shotaro12ORCID,Saito Katsuharu1,Sato Takahiro1,Sakuma Mei1,Fukai Satoshi1,Endo Eisei1,Sakamoto Wataru1ORCID,Saito Motonobu1ORCID,Saze Zenichiro1,Momma Tomoyuki1,Mimura Kosaku13ORCID,Kono Koji1

Affiliation:

1. Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan

2. Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan

3. Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan

Abstract

TGFβ signaling in the tumor microenvironment (TME) drives immune evasion and is a negative predictor of immune checkpoint inhibitor (ICI) efficacy in colorectal cancer (CRC). TIM-3, an inhibitory receptor implicated in anti-tumor immune responses and ICI resistance, has emerged as an immunotherapeutic target. This study investigated TIM-3, M2 macrophages and the TGFβ-activated TME, in association with microsatellite instability (MSI) status and consensus molecular subtypes (CMSs). Transcriptomic cohorts of CRC tissues, organoids and xenografts were examined (n = 2240). TIM-3 and a TGFβ-inducible stromal protein, VCAN, were evaluated in CRC specimens using immunohistochemistry (n = 45). TIM-3 expression on monocytes and generated M2 macrophages was examined by flow cytometry. We found that the expression of HAVCR2 (TIM-3) significantly correlated with the transcriptional signatures of TGFβ, TGFβ-dependent stromal activation and M2 macrophage, each of which were co-upregulated in CMS4, CMS1 and MSI CRCs across all datasets. Tumor-infiltrating TIM-3+ immune cells accumulated in TGFβ-responsive cancer stroma. TIM-3 was increased on M2-polarized macrophages, and on monocytes in response to TGFβ treatment. In conclusion, we identified a close association between TIM-3 and M2-like polarization of macrophages in the TGFβ-rich TME. Our findings provide new insights into personalized immunotherapeutic strategies based on the TME for CRCs.

Funder

Japan Society for the Promotion of Science KAKENHI

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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