Abstract
Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response, but knowledge on the exact contribution of each immune cell subset is limited. We show that therapy-induced intratumoral CD8+ T cells recruited and skewed late-stage activated M1-like macrophages, which were critical for effective tumor control in two different murine models of cancer immunotherapy. The activated CD8+ T cells summon these macrophages into the tumor and their close vicinity via CCR5 signaling. Exposure of non-polarized macrophages to activated T cell supernatant and tumor lysate recapitulates the late-stage activated and tumoricidal phenotype in vitro. The transcriptomic signature of these macrophages is also detected in a similar macrophage population present in human tumors and coincides with clinical response to immune checkpoint inhibitors. The requirement of a functional co-operation between CD8+ T cells and effector macrophages for effective immunotherapy gives warning to combinations with broad macrophage-targeting strategies.
通过免疫疗法彻底清除肿瘤与完全协调的先天性和适应性免疫反应有关，但人们对每种免疫细胞亚群的确切贡献了解有限。我们的研究表明，在两种不同的癌症免疫疗法小鼠模型中，治疗诱导的瘤内CD8+ T细胞招募并偏向晚期活化的M1样巨噬细胞，这对有效控制肿瘤至关重要。活化的CD8+ T细胞通过CCR5信号将这些巨噬细胞召唤到肿瘤及其附近。将非极化巨噬细胞暴露于活化的T细胞上清液和肿瘤裂解液，可在体外再现晚期活化和杀瘤表型。这些巨噬细胞的转录组特征也能在人类肿瘤中的类似巨噬细胞群中检测到，并与免疫检查点抑制剂的临床反应相吻合。CD8+T细胞和效应巨噬细胞之间的功能性合作对有效的免疫疗法的要求为广泛的巨噬细胞靶向策略的联合提供了方向。
van Elsas MJ, Middelburg J, Labrie C, Roelands J, Schaap G, Sluijter M, Tonea R, Ovcinnikovs V, Lloyd K, Schuurman J, Riesenfeld SJ, Gajewski TF, de Miranda NFCC, van Hall T, van der Burg SH. Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy. Cancer Cell. 2024 Jun 10;42(6):1032-1050.e10. doi: 10.1016/j.ccell.2024.04.011. Epub 2024 May 16. PMID: 38759656.
