Research Article Requirement for Innate Immunity and CD90þ NK1.1 Lymphocytes to Treat Established Melanoma with Chemo-Immunotherapy

We sought to define cellular immune mechanisms of synergy between tumor-antigen–targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (aTRP1), a native melanoma differentiation antigen. We find that Fcg receptors are required for efficacy, showing that anti-tumor activity of combination therapy is immune mediated. Rag1/ mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not signif-icantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lym-phocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2gc/) are refractory to chemo-immunother-apy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1þ cells does not impair antitumor effect. Depletion of CD90þNK1.1 lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during com-bination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90þNK1.1 ILCs in chemo-immunotherapy. Cancer Immunol Res; 3(3); 296– 304. 2015 AACR