posted on 2024-02-08, 18:48authored byBrandie C. Taylor, Xiaopeng Sun, Paula I. Gonzalez-Ericsson, Violeta Sanchez, Melinda E. Sanders, Elizabeth C. Wescott, Susan R. Opalenik, Ann Hanna, Shu-Ting Chou, Luc Van Kaer, Henry Gomez, Claudine Isaacs, Tarah J. Ballinger, Cesar A. Santa-Maria, Payal D. Shah, Elizabeth C. Dees, Brian D. Lehmann, Vandana G. Abramson, Jennifer A. Pietenpol, Justin M. Balko
Combination anti-PDL1 and anti-NKG2A treatment in genetically modified tumors
Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
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.
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.This article is featured in Selected Articles from This Issue, p. 201