부산대학교 도서관

Simple Summary: TGFβ and TIM-3 have been implicated in driving immune evasion and poor response to anti-PD-1/PD-L1 immune checkpoint inhibitors (ICIs). Using large-scale transcriptomic data analysis, followed by immunohistochemistry and in vitro experiments, we demonstrated a strong link between TIM-3 and M2-like polarization of macrophages in the TGFβ-rich tumor microenvironment in colorectal cancer (CRC). We found that the transcriptional signatures of TIM-3, M2 macrophage and TGFβ-responsive stromal activation were specifically derived from the stromal components and were correlated with each other, and that they were robustly upregulated in CMS4, CMS1 and MSI CRCs. Our study suggests that the blockade of TGFβ or TIM-3, combined with ICIs, may be a promising strategy to circumvent the resistance to current ICIs for CMS4, CMS1 and MSI CRCs, where TIM-3 is highly expressed along with increased TGFβ. 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. [ABSTRACT FROM AUTHOR]