免疫疗法
三阴性乳腺癌
MHC I级
癌症研究
主要组织相容性复合体
CD8型
乳腺癌
免疫学
癌症免疫疗法
T细胞
免疫系统
生物
医学
癌症
内科学
作者
Brandie 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 Gómez,Claudine Isaacs,Tarah J. Ballinger,Cesar A. Santa-Maria,Payal D. Shah,Elizabeth Claire Dees,Brian D. Lehmann,Vandana G. Abramson,Jennifer A. Pietenpol,Justin M. Balko
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2023-10-03
卷期号:14 (2): 290-307
被引量:3
标识
DOI:10.1158/2159-8290.cd-23-0519
摘要
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.
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