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Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8+ T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8+ T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4+ macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4+ cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments. [Display omitted] • Metastatic involvement of the serous body cavities portends worse ICB outcomes • Tim-4 levels on human macrophages correlate with reduced CD8+ CD39+ T cells • Tim-4+ macrophages sequester and impair proliferation of CD8+ T cells • Tim-4 blockade enhances the efficacy of ICB and adoptive T cell therapy in mice Chow et al. demonstrate that metastatic involvement of the pleural and peritoneal cavities is associated with poor ICB efficacy in patients with cancer. Tim-4+ cavity-resident macrophages directly impair CD8 T cell function, and Tim-4 blockade enhances the efficacy of ICB and adoptive T cell therapy in mice. [ABSTRACT FROM AUTHOR]

Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4+ T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants. [Display omitted] • T cell immunotherapies can eliminate antigenically heterogeneous tumors • Neutrophils are recruited and are responsible for killing antigen loss variants • Anti-tumorigenic neutrophils display a distinct genotype and phenotype • Neutrophil activation is observed in patients treated with T cell immunotherapies The eradication of antigenically heterogeneous tumors by T cell immunotherapies requires neutrophils. [ABSTRACT FROM AUTHOR]