Browsing by Author "Chou, S-T"

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NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer
(American Association for Cancer Research Inc., 2024) Taylor, BC; Sun, X; Gonzalez-Ericsson, PI; Sanchez, V; Sanders, ME; Wescott, EC; Opalenik, SR; Hanna, A; Chou, S-T; Van, Kaer, L; Gomez, H; Isaacs, C; Ballinger, TJ; Santa-Maria, CA; Shah, PD; Dees, EC; Lehmann, BD; Abramson, VG; Pietenpol, JA; Balko, JM
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 antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (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. SIGNIFICANCE: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti–PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance.