Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy
Marit J van Elsas, Jim Middelburg, Camilla Labrie, Jessica Roelands, Gaby Schaap, Marjolein Sluijter, Ruxandra Tonea, Vitalijs Ovcinnikovs, Katy A. Lloyd, Janine Schuurman, Samantha J. Riesenfeld, Thomas F. Gajewski, Noel F.C.C. de Miranda, Thorbald van Hall, Sjoerd H. van der Burg
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.