title: Cytokine therapy reverses NK cell anergy in MHC-deficient tumors.
abstract: Various cytokines have been evaluated as potential anticancer drugs; however, most cytokine trials have shown relatively low efficacy. Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors. NK cell anergy was accompanied by impaired early signal transduction and was locally imparted by the presence of MHC class I-deficient tumor cells, even when such cells were a minor population in a tumor mixture. These results demonstrate that MHC class I-deficient tumor cells can escape from the immune response by functionally inactivating NK cells, and suggest cytokine-based immunotherapy as a potential strategy for MHC class I-deficient tumors. These results suggest that such cytokine therapies would be optimized by stratification of patients. Moreover, our results suggest that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.
authors.forename: Michele
authors.initials: M
authors.lastname: Ardolino
authors.forename: Camillia S
authors.initials: CS
authors.lastname: Azimi
authors.forename: Alexandre
authors.initials: A
authors.lastname: Iannello
authors.forename: Troy N
authors.initials: TN
authors.lastname: Trevino
authors.forename: Lucas
authors.initials: L
authors.lastname: Horan
authors.forename: Lily
authors.initials: L
authors.lastname: Zhang
authors.forename: Weiwen
authors.initials: W
authors.lastname: Deng
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Ring
authors.forename: Suzanne
authors.initials: S
authors.lastname: Fischer
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D017635:Clonal Anergy; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000235:genetics; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D019139:Tumor Escape; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D020382:Interleukin-18; D007376:Interleukin-2; D018664:Interleukin-12