title: Enhanced Tumor Control with Combination mTOR and PD-L1 Inhibition in Syngeneic Oral Cavity Cancers.
abstract: Significant subsets of patients with oral cancer fail to respond to single-agent programmed death (PD) blockade. Syngeneic models of oral cancer were used to determine if blocking oncogenic signaling improved in vivo responses to PD-L1 monoclonal antibody (mAb). Anti-PD-L1 enhanced durable primary tumor control and survival when combined with mTOR (rapamycin), but not in combination with MEK inhibition (PD901) in immunogenic MOC1 tumors. Conversely, PD-L1 mAb did not enhance tumor control in poorly immunogenic MOC2 tumors. Rapamycin enhanced expansion of peripheral antigen-specific CD8 T cells and IFNγ production following ex vivo antigen stimulation. More CD8 T cells infiltrated and were activated after PD-L1 mAb treatment in mice with immunogenic MOC1 tumors, which were stable or increased by the addition of rapamycin, but suppressed when PD901 was added. Rapamycin increased IFNγ production capacity in peripheral and tumor-infiltrating CD8 T cells. In vivo antibody depletion revealed a CD8 T-cell-dependent, and not NK cell-dependent mechanism of tumor growth inhibition after treatment with rapamycin and PD-L1 mAb, ruling out significant effects from NK cell-mediated antibody-dependent cellular cytotoxicity. Rapamycin also enhanced IFNγ or PD-L1 mAb treatment-associated induction of MHC class I expression on MOC1 tumor cells, an effect abrogated by depleting infiltrating CD8 T cells from the tumor microenvironment. These data conflict with traditional views of rapamycin as a universal immunosuppressant, and when combined with evidence of enhanced antitumor activity with the combination of rapamycin and PD-L1 mAb, suggest that this treatment combination deserves careful evaluation in the clinical setting. Cancer Immunol Res; 4(7); 611-20. ©2016 AACR.
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Moore
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
authors.forename: Harrison A
authors.initials: HA
authors.lastname: Cash
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
authors.forename: Andria M
authors.initials: AM
authors.lastname: Caruso
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Washington University in St. Louis School of Medicine, St. Louis, Missouri.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Uppaluri
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institutes of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland. Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland. clint.allen@nih.gov.
authors.forename: Clint T
authors.initials: CT
authors.lastname: Allen
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D058990:Molecular Targeted Therapy; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases