CKLF‐like MARVEL transmembrane domain‐containing superfamily 8 (CMTM8) promotes Notch signalling to maintain CD8 ⁺ T cell‐ and NK cell‐dependent tumour immune escape

Background and Purpose The CKLF‐like MARVEL transmembrane domain containing superfamily (CMTM) has an important role in tumour immunity. The role of CMTM8 in tumour immune microenvironment (TIME) remains unknown. The aim was to investigate the relationship between CMTM8 and antitumour immunity. Experimental Approach Lentiviral system was established to achieve functional edition of CMTM8. CMTM8 in tumour progression and TIME was investigated by using subcutaneous xenograft mice tumour models. CMTM8 targeting was achieved using an adeno‐associated virus (AAV)–based shRNA vector. Key Results Clinical data showed that high expression of CMTM8 in melanoma and colorectal cancer is associated with lower patient survival rates and poorer intra‐tumoural immune cell infiltration. Mouse melanoma and colon cancer models, CMTM8 expression markedly accelerated tumour growth by regulating intra‐tumoural infiltration of CD8 + T cells and NK cells. RNA sequencing of CMTM8‐overexpressed B16 cells showed that Notch pathway is significantly up‐regulated, and blockade of Notch pathway in vivo resulted in lower intra‐tumoural infiltration of CD8 + T cells and NK cells, and confined tumour progression. CMTM8 could down‐regulate the EGFR pathway by promoting endocytosis of EGFR, possible leading to higher expression of Notch1. Similar this observed in human colon cancer in a PBMC‐engrafted NCG model. Besides, we developed the CMTM8‐targeting adeno‐associated virus, which effectively up‐regulated intra‐tumoural infiltration of CD8 + T cells and NK cells and inhibited tumour growth. Conclusion and Implications Tumour‐intrinsic CMTM8 could possibly regulate TIME via EGFR‐Notch axis and that CMTM8 is a promising target for tumour immunotherapy, especially for treatment of colorectal cancer or melanoma patients.