T CELL IMMUNOTHERAPIES TRIGGER NEUTROPHIL ACTIVATION TO ELIMINATE TUMOR ANTIGEN ESCAPE VARIANTS

BackgroundTargeted immune-based therapies such as adoptive T cell transfer (ACT) are often ineffective because tumors evolve over time and under selective pressure display antigen loss variant clones. A classic example in melanoma is de-differentiation and loss of expression of antigenic proteins. Therapies that activate multiple branches of the immune system may eliminate such escape variantsMethodsHere we show that melanoma-specific CD4+ ACT therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate large melanoma tumors with clonal escape variants.ResultsEarly on-target recognition of melanoma antigens by adoptively transferred tumor-specific CD4+ T cells was required. Surprisingly, however, complete tumor eradication was partially dependent on neutrophils. Supporting these findings, extensive neutrophil activation and neutrophil extracellular traps were found in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade.ConclusionsOur findings uncover a novel interplay between T cells mediating the initial tumor- and tissue-specific immune response, and neutrophils mediating tumor destruction of antigen loss variants.Ethics ApprovalAll tissues were collected at MSKCC following study protocol approval by the MSKCC Institutional Review Board. All mouse procedures were performed in accordance with institutional protocol guidelines at Memorial Sloan-Kettering Cancer Center (MSKCC) under an approved protocol.</jats:sec

T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants.

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