Combination regimens incorporating chemotherapy and anti-tumor monoclonal antibodies are in wide clinical use but mechanisms of action are unknown. A better mechanistic understanding would enhance clinical protocols. We treated established melanomas with cyclophosphamide (CY) in combination with an antibody targeting tyrosinase related protein 1 (TRP1), a melanoma differentiation antigen. Therapeutic activity is immune mediated as Fc gamma receptors are required for efficacy. Immune responses can be innate or adaptive and, using Rag 1-/- mice deficient in B and T lymphocytes, we find that the innate immune system is sufficient for tumor clearance. Classic effector cells of the innate immune system include lymphocytes, of which the largest population is NK1.1+ natural killer (NK) cells, and macrophages. NK cells, surprisingly, are not critical as depletion of NK1.1+ cells did not significantly impair anti-tumor effect. In contrast, elimination of non-classical NK1.1- innate lymphocytes, through deletion of the Interleukin 2 (IL2) receptor common gamma chain required for their development, or depletion via antibody targeting pan lymphocyte marker Thy1.2 in Rag 1-/- mice, impairs efficacy of combination therapy. Non-classical NK1.1-Thy1.2+ innate lymphocytes have been implicated in leukocyte infiltration into tissues. We find that depletion of Thy1.2+ cells diminishes entry of Thy 1.2- leukocytes into melanomas treated with chemotherapy and alters the phenotype of infiltrating myeloid cells. Thus, our data highlights a novel role for non-classical innate lymphocytes in the treatment of solid malignancies with monoclonal antibody and chemotherapy.

Citation Format: Marina Moskalenko, Michael Pan, Daigo Hashimoto, Arthur Mortha, Sebastian G. Bernardo, Marylene Leboeuf, Alan Houghton, Jedd Wolchok, Steven Burakoff, Miriam Merad, Yvonne M. Saenger. Therapeutic efficacy of antitumor monoclonal antibodies combined with chemotherapy depends on innate immunity and NK1.1- innate lymphoid cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A43.