ena-STUDY-CANDIOLO CANCER INSTITUTE-07-12-2020-16:47:12:985-16
Immune checkpoint blockers instruct CD4 T cell dependent rejection of beta 2 microglobulin null mismatch repair deficient tumors
Tumor progression relies on the ability of malignant cells to elude immune surveillance. Molecular defects in Beta 2-Microglobulin (B2M) determine immune checkpoint inhibitor (ICPi) resistance in melanoma and lung cancers, but not in MMR deficient (MMRd) colorectal tumors where inactivation of B2M is frequently observed. The molecular mechanisms underlying this phenotype are poorly understood. To address this, we inactivated B2M and MLH1, a critical component of MMR, in colorectal, pancreatic and breast murine cancer cells, thus generating MMRd tumors with impaired antigen presenting machinery (APM). B2M inactivation re-established tumorigenicity in immune competent mice, despite MMR deficiency. However, anti-PD-1 alone or in combination with anti-CTLA-4 caused rejection of MMRd tumors defective in B2M expression. Mechanistically, efficacy of ICPi against MMRd B2M deficient murine tumors did not require CD8+ T cells but relied on the presence of CD4+ T cells. Genetic alterations in the APM are enriched in human MMRd tumors, however we found that B2M low expressing tumors carry more intra-tumoral CD3+ CD8- T cells than those with higher B2M expression. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors and we identify a unique role for tumor-specific CD4+ T cells in instructing immune rejection.
Tumor progression relies on the ability of malignant cells to elude immune surveillance. Molecular defects in Beta 2-Microglobulin (B2M) determine immune checkpoint inhibitor (ICPi) resistance in melanoma and lung cancers, but not in MMR deficient (MMRd) colorectal tumors where inactivation of B2M is frequently observed. The molecular mechanisms underlying this phenotype are poorly understood. To address this, we inactivated B2M and MLH1, a critical component of MMR, in colorectal, pancreatic and breast murine cancer cells, thus generating MMRd tumors with impaired antigen presenting machinery (APM). B2M inactivation re-established tumorigenicity in immune competent mice, despite MMR deficiency. However, anti-PD-1 alone or in combination with anti-CTLA-4 caused rejection of MMRd tumors defective in B2M expression. Mechanistically, efficacy of ICPi against MMRd B2M deficient murine tumors did not require CD8+ T cells but relied on the presence of CD4+ T cells. Genetic alterations in the APM are enriched in human MMRd tumors, however we found that B2M low expressing tumors carry more intra-tumoral CD3+ CD8- T cells than those with higher B2M expression. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors and we identify a unique role for tumor-specific CD4+ T cells in instructing immune rejection.