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

Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates anti-tumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of NK cells in IFNγ dependent manner. Using spatial technologies, 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 require NKG2A to suppress NK cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials.