T Cell Immunotherapies Trigger Neutrophil Activation to Eliminate Tumor Antigen Escape Variants

Targeted immune therapies such as adoptive T cell transfer (ACT) are often ineffective because tumors evolve over time under selective pressure to display antigen loss variant.  A classic example is de-differentiation and loss of expression of antigenic proteins. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here we show that melanoma-specific CD4+ ACT therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas that contain clonal escape variants. As expected, early on-target recognition of melanoma antigens by adoptively transferred tumor-specific CD4+ T cells was required. Surprisingly, complete tumor eradication was partially dependent on neutrophils. Supporting these findings, extensive neutrophil extracellular traps were found in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Our 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.