CD4 T cell dependent rejection of beta 2 microglobulin null mismatch repair deficient tumors.

Inactivation of Beta 2-Microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitor (ICPi) in melanoma and lung cancers. In contrast, B2M loss does not appear to impact response to ICPi in Mismatch Repair deficient (MMRd) colorectal tumors where biallelic inactivation of B2M is frequently observed. We inactivated B2M in multiple murine MMRd cancer models. While MMRd cells would not readily grow in immunocompetent mice, MMRd B2M null cells were tumorigenic and regressed when treated with anti-PD-1 and anti-CTLA-4. The efficacy of ICPi against MMRd B2M null tumors did not require CD8+ T cells but relied on the presence of CD4+ T cells. Human tumors expressing low level of B2M display increased intra-tumoral CD4+ T cells. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors and we identify a unique role for CD4+ T cells in tumor rejection.