CMTM6 expression in M2 macrophages is a potential predictor of PD-1/PD-L1 inhibitor response in colorectal cancer

Abstract

Background CMTM6 is a novel key regulator of PD-L1. High expression of both CMTM6 and PD-L1 may predict the benefit of PD-1 axis blockade in lung cancer. We aimed to investigate the expression pattern of CMTM6 between mismatch repair-defective (dMMR) and mismatch repair-proficient (pMMR) colorectal cancer (CRC) tissues and assess its correlation with the response to PD-1/PD-L1 pathway blockade. Methods Immunohistochemistry (IHC) was used to analyze CMTM6 and PD-L1 expression and immune cell density in dMMR/pMMR CRC. Quantitative multiplex immunofluorescence (IF) was performed to detect CMTM6, PD-L1, CD4, CD8, CD68 and CD163 expression in CRC patients treated with PD-1/PD-L1 inhibitors. Result IHC analysis showed that CMTM6 and PD-L1 were both expressed in tumor cells (TCs) and invasion front immune cells (ICs). CMTM6 and PD-L1 expression and CD4+, CD8+, CD68+ or CD163+ cell density were significantly higher in dMMR CRC patients than in pMMR CRC patients. CMTM6 expression was positively correlated with PD-L1 expression and CD163+ M2 macrophage density in dMMR CRC. IF analysis showed that the coexpression rate of CMTM6/PD-L1 and the expression rate of CMTM6 in CD8+ T cells and CD163+ M2 macrophages were significantly increased in the group that exhibited clinical benefit. CMTM6 expression in M2 macrophages was identified as the best biomarker for predicting the responsiveness to PD-1/PD-L1 inhibitors. Conclusions CMTM6 expression in M2 macrophages may predict the PD-1/PD-L1 inhibitor response rate in CRC patients more accurately than dMMR/microsatellite instability-high (MSI-H) status. It can also identify pMMR CRC patients who could benefit from PD-1/PD-L1 inhibitors.

Co-Expression with Membrane CMTM6/4 on Tumor Epithelium Enhances the Prediction Value of PD-L1 on Anti-PD-1/L1 Therapeutic Efficacy in Gastric Adenocarcinoma

“…A recent study indicates that CMTM6 is expressed on CD8 + T cells and CD163 + M2 macrophages in colorectal cancer tissues. Its expression in T cells and M2 macrophage is associated with clinical benefit and response to immunotherapy [27]. Another study found the expression of CMTM6 mainly on CD68 positive macrophages in the non-small-cell lung cancer (NSCLC), and its expression is correlated with longer overall survival in the patients with immunotherapy [28].…”

CMTM Family and Gastrointestinal Tract Cancers: A Comprehensive Review

“… B7 family, Vimentin, PD-L1 [ 77–81 ] GC Higher a useful prognostic indicator [ 39 , 40 ] CRC Higher Associated with an active immune microenvironment, a favorable prognosis. [ 84 , 85 ] NSCLC Lower in lung adenocarcinoma Correlated with PD-L1 expression and immune cells infiltration [ 4 , 86–89 ] HNSCC Higher Promotes cell proliferation and invasion; drives cisplatin resistance; Induced M2-like macrophages polarization Wnt/β-catenin, TGFβ; ENO-1/AKT/GSK3β; ERK1/2 [ 90–94 ] Gliomas Higher Regulating T cell activation and antitumor and responses [ 7 ] Undifferentiated pleomorphic sarcoma Correlated with the strong expression of PD-L1 [ 95 ] Glioblastoma Higher (mRNA)* - [ 36 ] CMTM7 HCC Lower Inhibits cell growth and migration …”

“…75 Meanwhile, the expression status of CMTM6 in M2 macrophages may more accurately predict the drug response to PD-1/PD-L1 inhibitors in CRC patients. 85 To date, the roles of other CMTM members in CRC, except for CMTM3, 4, and 6, are largely unknown.…”

Suppression of tumor/host intrinsic CMTM6 drives anti-tumor cytotoxicity in a PD-L1 independent manner

“…(18,19,(21)(22)(23)(24). Remarkably, CMTM6/PD-L1 coexpression suggested a poorer prognosis (20,(25)(26)(27), but instead a better prognosis when ICB therapies intervened (28)(29)(30). However, some contradictory findings have also been reported, indicating a complex role for CMTM6 in clinical cancers such as non-small cell lung cancer (NSCLC) (31)(32)(33).…”