CD4 T Cell–Dependent Rejection of Beta-2 Microglobulin Null Mismatch Repair–Deficient Tumors

Abstract

Inactivation of beta-2 microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitors (ICPi) in melanoma and lung cancers. In contrast, <i>B2M</i> loss does not appear to affect response to ICPis in mismatch repair-deficient (MMRd) colorectal tumors where biallelic inactivation of <i>B2M</i> is frequently observed. We inactivated <i>B2m</i> in multiple murine MMRd cancer models. Although MMRd cells would not readily grow in immunocompetent mice, MMRd <i>B2m</i> null cells were tumorigenic and regressed when treated with anti-PD-1 and anti-CTLA4. The efficacy of ICPis against MMRd <i>B2m</i> null tumors did not require CD8⁺ T cells but relied on the presence of CD4⁺ T cells. Human tumors expressing low levels of B2M display increased intratumoral 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. SIGNIFICANCE: <i>B2M</i> alterations, which impair antigen presentation, occur frequently in microsatellite-unstable colorectal cancers. Although in melanoma and lung cancers <i>B2M</i> loss is a mechanism of resistance to immune checkpoint blockade, we show that MMRd tumors respond to ICPis through CD4⁺ T-cell activation.<i>This article is highlighted in the In This Issue feature, p. 1601</i>.