Taylor, Brandie C.Sun, XiaopengGonzalez-Ericsson, Paula I.Sanchez, VioletaSanders, Melinda E.Wescott, Elizabeth C.Opalenik, Susan R.Hanna, AnnChou, Shu-TingVan Kaer, LucGomez, HenryIsaacs, ClaudineBallinger, Tarah J.Santa-Maria, Cesar A.Shah, Payal D.Dees, Elizabeth C.Lehmann, Brian D.Abramson, Vandana G.Pietenpol, Jennifer A.Balko, Justin M.2024-06-182024-06-182024Taylor BC, Sun X, Gonzalez-Ericsson PI, et al. NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer. Cancer Discov. 2024;14(2):290-307. doi:10.1158/2159-8290.CD-23-0519https://hdl.handle.net/1805/41596Despite 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalB7-H1 antigenImmunotherapyTriple negative breast neoplasmsArticle