Jardim and Bica et al. demonstrated that i.t. myeloid cell treatment (MCT), a combination of TLR3 and CD40 agonists, effectively reprogrammed TAMs to adopt an antitumor phenotype (iNOS+ and CD38+) and induced tumor control in an orthotopic E0771 mouse breast cancer model. MCT-activated TAMs were transient and required secondary injections for sustained phenotypic and functional maintenance. MCT-induced TAMs promoted antigen presentation and effector CD8+ T cell recruitment, ultimately resulting in long-term tumor eradication. ROS and TNFα acted as potent antitumor effector molecules of MCT-activated TAMs in vivo.
Contributed by Shishir Pant
ABSTRACT: Tumor-associated macrophages (TAMs) exhibit a dual role in tumor progression and antitumor immunity. However, understanding the functional states and molecular mechanisms of antitumor TAMs remains a challenge. Herein, we show that intratumoral administration of a combination of agonists against TLR3 and CD40 (hereafter termed myeloid cell treatment, MCT) reprogrammed TAMs in situ to adopt a protective antitumor phenotype in an orthotopic mouse breast cancer model, and that this led to tumor regression. Single-cell RNA sequencing of TAMs from different tumor stages and post-MCT revealed a transient antitumor TAM phenotype, present at 12h post-MCT, characterized by markers such as iNOS and CD38, which was replaced by TAMs co-expressing tumor-limiting and promoting features by 72h post-MCT. Maintenance of antitumor TAMs required repeated MCT administration, and this promoted the activation of CD8+ T cells and long-term tumor eradication. Mechanistically, ROS and TNF-_ were pivotal in TAM-mediated tumor control. Our findings uncover the vulnerability of transient TAM reprogramming and show that it can be overcome by repeated MCT administrations to sustain efficient antitumor immune responses.
Author Info: (1) Instituto de Medicina Molecular Joo Lobo Antunes, Portugal. (2) Gulbenkian Institute for Molecular Medicine, Lisboa, Portugal. (3) Cedars-Sinai Medical Center, Lisbon, Portuga
Author Info: (1) Instituto de Medicina Molecular Joo Lobo Antunes, Portugal. (2) Gulbenkian Institute for Molecular Medicine, Lisboa, Portugal. (3) Cedars-Sinai Medical Center, Lisbon, Portugal. (4) Instituto de Medicina Molecular Jọo Lobo Antunes, Lisboa, Portugal. (5) Champalimaud Foundation, Lisboa, Portugal. (6) Instituto de Medicina Molecular Joo Lobo Antunes, Lisboa, Portugal. (7) Instituto de Medicina Molecular Joo Lobo Antunes, Lisboa, Portugal. (8) Gulbenkian Institute for Molecular Medicine, Lisboa, Portugal. (9) Instituto de Medicina Molecular Joo Lobo Antunes, Lisboa, Portugal. (10) Instituto de Medicina Molecular Joo Lobo Antunes, Lisboa, Portugal. (11) Instituto de Medicina Molecular Joo Lobo Antunes, Lisboa, Portugal. (12) Gulbenkian Institute for Molecular Medicine, Lisboa, Portugal. (13) Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan. (14) Instituto de Biologia Experimental Tecnolgica, Portugal. (15) Instituto de Biologia Experimental Tecnolgica, Portugal. (16) Center for Immunology of Marseille Luminy, Marseille, France. (17) Instituto de Medicina Molecular Joo Lobo Antunes, Lisboa, Portugal. (18) Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. (19) Gulbenkian Institute for Molecular Medicine, Lisboa, Portugal. (20) Gulbenkian Institute for Molecular Medicine, Lisboa, Portugal. (21) Instituto de Medicina Molecular Joo Lobo Antunes, Lisboa, Portugal.
