MAP7D2 reduces CD8+cytotoxic T lymphocyte infiltration through MYH9-HMGB1 axis in colorectal cancer

Immune checkpoint inhibitors (ICIs) represent a new para-digm in cancer immunotherapy, but can be largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs) in colorectal cancer (CRC) patients with microsatellite stable (MSS) tumors. Here, through next-generation sequ-encing, we identify microtubule-associated protein 7 domain 2 (MAP7D2) as an exploitable therapeutic maneuver to imp-rove the efficacy of ICIs for MSS CRC therapy. In human CRC tissues, MAP7D2 expression is significantly increased in MSS CRC, and MAP7D2 adversely correlates with the presence of antitumor T lymphocytes. In vitro and in vivo experiments demonstrate that MAP7D2 knockdown significantly increases the infiltration of CD8+ CTLs, thereby inhibiting tumor pro-gression and improving the efficacy of ICIs in MSS CRC mu -rine models. Mechanistically, MAP7D2 interacts with MYH9 and protects it from ubiquitin-mediated degradation, subse-quently decreasing the secretion of HMGB1, which suppresses the infiltration of CD8+ CTLs in MSS CRC. These findings highlight the importance of MAP7D2 in determining the infil-tration of CD8+ CTLs and indicate that targeting MAP7D2 in MSS CRC may present a novel antitumor immunotherapy.

Automated summary

Through next-generation sequencing, we identified MAP7D2 as a potential therapeutic target to improve the efficacy of immune checkpoint inhibitors (ICIs) for microsatellite stable (MSS) colorectal cancer (CRC) therapy. MAP7D2 expression was increased in MSS CRC and negatively correlated with the presence of antitumor T lymphocytes. Knockdown of MAP7D2 significantly enhanced CD8+ CTLs infiltration and improved the efficacy of ICIs in MSS CRC murine models. Targeting MAP7D2 may present a novel approach for antitumor immunotherapy in MSS CRC.