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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2021-11, Vol.70 (11), p.3235-3248
• Main Authors: Wu, Xuehui, Lan, Xiaoliang, Hu, Wanming, Zhang, Wanning, Lai, Xiangmeng, Xu, Shaowan, Li, Jiaoying, Qiu, Weihao, Wang, Wei, Xiao, Jianbiao, Wang, Feifei, Ding, Yanqing, Liang, Li
• Format: Article
• Language: English
• Subjects: Cancer Research; CD163 antigen; CD4 antigen; CD8 antigen; Cell density; Colorectal cancer; Colorectal carcinoma; Immunofluorescence; Immunohistochemistry; Immunology; Lung cancer; Lymphocytes T; Macrophages; Medicine; Medicine & Public Health; Microsatellite instability; Mismatch repair; Oncology; Original; Original Article; Patients; PD-1 protein; PD-L1 protein; Tumor cells
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-021-02931-6

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.