NKG2A is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogenous Triple Negative Breast Cancer

Abstract

Although immune checkpoint inhibition (ICI) has proven successful in treating cancer, patients with triple-negative breast cancer (TNBC) often develop therapy resistance, and the underlying mechanisms remain unclear. MHC-I expression is crucial for antigen presentation and T-cell-directed immunotherapy responses. The studies presented here demonstrates that TNBC patients exhibit intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I abolishes antitumor immunity and ICI response, while intratumor MHC-I heterogeneity results in increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Spatial technologies reveal that MHC-I heterogeneity is associated with clinical resistance to anti-PD-L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors necessitate NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, contingent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These findings suggest that implementing similar strategies may enhance patient benefit in clinical trials.