title: Requirement for innate immunity and CD90⁺ NK1.1⁻ lymphocytes to treat established melanoma with chemo-immunotherapy.
abstract: 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 (αTRP1), a native melanoma differentiation antigen. We find that Fcγ receptors are required for efficacy, showing that antitumor 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 significantly 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 lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2γc(-/-)) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1⁺ cells does not impair antitumor 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⁻ ILCs in chemo-immunotherapy.
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Marina
authors.initials: M
authors.lastname: Moskalenko
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Pan
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ellen H
authors.initials: EH
authors.lastname: de Moll
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Hashimoto
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Arthur
authors.initials: A
authors.lastname: Mortha
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Marylene
authors.initials: M
authors.lastname: Leboeuf
authors.affiliation: Department of Otolaryngology, Baylor College of Medicine, Houston, Texas.
authors.forename: Padmini
authors.initials: P
authors.lastname: Jayaraman
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bernardo
authors.affiliation: Department of Otolaryngology, Baylor College of Medicine, Houston, Texas.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jedd
authors.initials: J
authors.lastname: Wolchok
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Medicine, Columbia University Medical Center, New York, New York. Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York. yms4@cumc.columbia.edu.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Saenger
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000950:Antigens, Ly / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D007113:Immunity, Innate; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D010088:Oxidoreductases / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D018800:Thy-1 Antigens / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D017452:Receptors, IgG; D018800:Thy-1 Antigens; D003520:Cyclophosphamide; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1