Van Elsas et al. elucidated a critical role for M1-like macrophages (MΦs) in tumor control, and demonstrated that this population depended on intratumoral CD8+ T cells. These cells attracted MΦs via the CCR5 signaling axis and, in concert with TLR4 stimulation, promoted acquisition of the iNOS+ M1 phenotype through secreted factors, including IFNγ. ScRNAseq revealed an inflammatory, motile, late-stage activated MΦ population that was associated with ICB-responsiveness both in mice and patients with breast cancer. In addition to tumor cell killing by phagocytosis, this iNOS+ population may function by depleting tumor cells of the critical nutrient L-arginine.
Contributed by Morgan Janes
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.
Author Info: (1) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (2) Department of Medical Oncology, Oncode Institute, Leiden
Author Info: (1) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (2) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (3) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (4) Department of Pathology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (5) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (6) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (7) Department of Pathology, University of Chicago, Chicago, IL 60637, USA; Pritzker School of Molecular Engineering, Chicago, IL 60637, USA. (8) Genmab, Utrecht 3584CT, the Netherlands. (9) Genmab, Utrecht 3584CT, the Netherlands. (10) Genmab, Utrecht 3584CT, the Netherlands. (11) Pritzker School of Molecular Engineering, Chicago, IL 60637, USA. (12) Department of Pathology, University of Chicago, Chicago, IL 60637, USA. (13) Department of Pathology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (14) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. (15) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. Electronic address: shvdburg@lumc.nl.
