title: Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model.
abstract: IL-15 has potential as an immunotherapeutic agent for cancer treatment because of its ability to effectively stimulate CD8 T cell, natural killer T cell, and natural killer cell immunity. However, its effectiveness may be limited by negative immunological checkpoints that attenuate immune responses. Recently a clinical trial of IL-15 in cancer immunotherapy was initiated. Finding strategies to conquer negative regulators and enhance efficacy of IL-15 is critical and meaningful for such clinical trials. In a preclinical study, we evaluated IL-15 combined with antibodies to block negative immune regulator cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in an established murine transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 prostate tumor model. IL-15 treatment resulted in a significant prolongation of survival in tumor-bearing animals. Coadministration of anti-PD-L1 or anti-CTLA-4 singly with IL-15 did not improve animal survival over that of IL-15 alone. However, simultaneous administration of IL-15 with anti-CTLA-4 and anti-PD-L1 was associated with increased numbers of tumor antigen-specific tetramer-positive CD8 T cells, increased CD8 T-cell tumor lytic activity, augmented antigen-specific IFN-γ release, decreased rates of tumor growth, and improved animal survival compared with IL-15 alone. Furthermore, triple combination therapy was associated with inhibition of suppressive functions of CD4(+)CD25(+) regulatory T cells and CD8(+)CD122(+) regulatory T cells. Thus, simultaneous blockade of CTLA-4 and PD-L1 protected CD4 and/or CD8 T-cell activity from these regulatory T cells. Combining the immune stimulatory properties of IL-15 with simultaneous removal of two critical immune inhibitory checkpoints, we showed enhancement of immune responses, leading to increased antitumor activity.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.forename: Jason C
authors.initials: JC
authors.lastname: Steel
authors.forename: Meili
authors.initials: M
authors.lastname: Zhang
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Rebecca
authors.initials: R
authors.lastname: Waitz
authors.forename: Marcella
authors.initials: M
authors.lastname: Fasso
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; D015848:Interleukin-5; D007371:Interferon-gamma