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Sustained macrophage reprogramming is required for CD8+ T cell–dependent long-term tumor eradication

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Summary:Tumor-associated macrophages (TAM) 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 after MCT revealed a transient antitumor TAM phenotype, present at 12 hours after MCT and characterized by markers such as inducible nitric oxide synthase and CD38, which was replaced by TAMs coexpressing tumor-limiting and tumor-promoting features by 72 hours after MCT. Maintenance of antitumor TAMs required repeated MCT administration, and this promoted the activation of CD8+ T cells and long-term tumor eradication. Mechanistically, reactive oxygen species and TNF-α 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.
Main Authors:Jardim, Carolina
Other Authors:Bica, Marta; Reis-Sobreiro, Mariana; Mota, Afonso Teixeira da; Lopes, Raquel; Ferreira-Pinto, Miguel Alexandre; Sousa, Neuza S.; Mensurado, Sofia; Boekhoff, Henning; Scolaro, Tommaso; Reugebrink, Maud; Gonçalves-Sousa, Natacha; Kubo, Hiroshi; Leites, Elvira; Morais, Vanessa A.; Silva-Santos, Bruno; Barbosa-Morais, Nuno; Serre, Karine
Year:2025
Country:Portugal
Document type:article
Access type:open access
Associated institution:Universidade de Lisboa
Language:English
Origin:Repositório da Universidade de Lisboa

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