We sought to define cellular immune mechanisms of synergy between tumor-antigen (TA) targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide (CY) in combination with an antibody targeting tyrosinase related protein 1 (αTRP1), a native melanoma differentiation antigen. We find that Fc-gamma receptors are required for efficacy, showing that anti-tumor activity of combination therapy is immune mediated. Rag 1-/- mice deficient in adaptive immunity are able to clear tumors and thus innate immunity is sufficient for efficacy. Further, previously treated wild type mice are not significantly protected against tumor re-induction, as compared to 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 non-classical innate lymphocytes (ILCs) due to deletion of the interleukin 2 receptor common gamma chain (IL2Rγ-/-) are refractory to chemo-immunotherapy. Classical natural killer (NK) lymphocytes are not critical for treatment, as depletion of NK1.1+ cells does not impair anti-tumor effect. Depletion of CD90+NK1.1- lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90+NK1.1- innate lymphocytes in chemo-immunotherapy.
- Received June 23, 2014.
- Revision received December 11, 2014.
- Accepted January 3, 2015.
- Copyright © 2015, American Association for Cancer Research.