title: IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase.
abstract: Murine and human mesothelioma tumors are susceptible to immunotherapy, particularly when immune adjuvants are delivered locally. We have shown that direct injection of IL-2 plus agonist anti-CD40 antibody induces regression of large mesothelioma tumors. These studies aimed to determine if NK cells contribute to IL-2/CD40 antibody-driven tumor eradication. We show that NK cells infiltrate developing mesothelioma tumors; however, their absence (in beige mice or in asialo GM(1) antibody-depleted C57BL/6J mice) does not alter tumor growth rates suggesting that they cannot function as effector cells in this microenvironment. Anti-CD40 antibody treatment did not alter the percent of NK cells in treated tumors or in draining lymph nodes (dLNs), and tumor resolution occurred in the absence of NK cells. However, a two-tumor model showed that NK cells contributed to CD40-driven systemic immunity leading to resolution of untreated distal tumors. IL-2 treatment led to increased proportions of NK cells in tumors and dLNs, and in the absence of NK cells, IL-2 lost its therapeutic effect. In contrast, the absence of NK cells did not reduce the anti-tumor activity of the IL-2/anti-CD40 antibody combination yet tumors recurred in NK-deficient mice and > 37% of tumor cell re-challenged mice were unable to provide protection, implying insufficient memory. Furthermore, untreated distal tumors in NK-depleted mice were less readily cured than in immunologically intact mice. These data show that NK cells infiltrate mesothelioma tumors, which, after local IL-2 and/or anti-CD40 antibody treatment, provide help for the acquisition and/or maintenance of systemic immunity and long-term effector/memory responses.
authors.affiliation: Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Bentley, Perth, Western Australia, 6102.
authors.forename: Connie
authors.initials: C
authors.lastname: Jackaman
authors.forename: Sally
authors.initials: S
authors.lastname: Lansley
authors.forename: Jane E
authors.initials: JE
authors.lastname: Allan
authors.forename: Bruce W S
authors.initials: BW
authors.lastname: Robinson
authors.forename: Delia J
authors.initials: DJ
authors.lastname: Nelson
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology / Q000627:therapeutic use; D019013:CD40 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D019013:CD40 Antigens; D007376:Interleukin-2; C527095:Klra7 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A