细胞毒性T细胞
免疫系统
癌症研究
免疫检查点
巨噬细胞
T细胞
CD8型
肿瘤微环境
抗原
免疫学
生物
免疫疗法
化学
PI3K/AKT/mTOR通路
细胞生物学
信号转导
体外
生物化学
作者
Larissa S. Carnevalli,Molly A. Taylor,Matthew King,Anna Coenen-Stass,Adina Hughes,Sigourney Bell,Theresa A. Proia,Yanjun Wang,Antonio Ramos‐Montoya,Neha Wali,Danielle Carroll,Maneesh Singh,Michele Moschetta,Pablo Morentin Gutierrez,Cristina Gardelli,Susan E. Critchlow,Teresa Klinowska,Stephen E. Fawell,Simon T. Barry
标识
DOI:10.1158/1535-7163.mct-20-0961
摘要
Abstract Suppressive myeloid cells mediate resistance to immune checkpoint blockade. PI3Kγ inhibition can target suppressive macrophages, and enhance efficacy of immune checkpoint inhibitors. However, how PI3Kγ inhibitors function in different tumor microenvironments (TME) to activate specific immune cells is underexplored. The effect of the novel PI3Kγ inhibitor AZD3458 was assessed in preclinical models. AZD3458 enhanced antitumor activity of immune checkpoint inhibitors in 4T1, CT26, and MC38 syngeneic models, increasing CD8+ T-cell activation status. Immune and TME biomarker analysis of MC38 tumors revealed that AZD3458 monotherapy or combination treatment did not repolarize the phenotype of tumor-associated macrophage cells but induced gene signatures associated with LPS and type II INF activation. The activation biomarkers were present across tumor macrophages that appear phenotypically heterogenous. AZD3458 alone or in combination with PD-1–blocking antibodies promoted an increase in antigen-presenting (MHCII+) and cytotoxic (iNOS+)-activated macrophages, as well as dendritic cell activation. AZD3458 reduced IL-10 secretion and signaling in primary human macrophages and murine tumor-associated macrophages, but did not strongly regulate IL-12 as observed in other studies. Therefore, rather than polarizing tumor macrophages, PI3Kγ inhibition with AZD3458 promotes a cytotoxic switch of macrophages into antigen-presenting activated macrophages, resulting in CD8 T-cell–mediated antitumor activity with immune checkpoint inhibitors associated with tumor and peripheral immune activation.
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