title: Immune-Stimulatory Effects of Rapamycin Are Mediated by Stimulation of Antitumor γδ T Cells.
abstract: The FDA-approved mTOR inhibitor rapamycin mediates important immune effects, but its contributions to the anticancer effects of the drug are unclear. Here we report evidence that rapamycin-mediated cancer protection relies upon stimulation of γδ T cells. In a well-established mouse model of carcinogen and inflammation-driven skin carcinogenesis, IFNγ recruited γδ TCRmidT cells to the epidermis where rapamycin boosted their perforin-dependent antitumor properties. These antitumor cells were mostly Vγ5-Vγ4-Vγ1-in phenotype. IFNγ signals were required in both hematopoietic and nonhematopoietic cells for rapamycin to optimally promote epidermal infiltration of γδ TCRmidT cells, as mediated by CXCR3-CXCL10 interactions, along with the antitumor effects of these cells. In mouse xenograft models of human squamous cell carcinoma, rapamycin improved human γδ T-cell-mediated cancer cell killing. Our results identify immune mechanisms for the cancer prevention and treatment properties of rapamycin, challenging the paradigm that mTOR inhibition acts primarily by direct action on tumor cells. Cancer Res; 76(20); 5970-82. ©2016 AACR.
authors: Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio (UTHSCSA), San Antonio, Texas. Department of Medicine, UTHSCSA, San Antonio, Texas.
authors: Vinh
authors: V
authors: Dao
authors: Department of Medicine, UTHSCSA, San Antonio, Texas. Xiangya School of Medicine, Central South University, Changsha, Hunan, P.R. China.
authors: Yang
authors: Y
authors: Liu
authors: Department of Medicine, UTHSCSA, San Antonio, Texas.
authors: Srilakshmi
authors: S
authors: Pandeswara
authors: Cancer Therapy & Research Center, UTHSCSA, San Antonio, Texas. Department of Urology, UTHSCSA, San Antonio, Texas.
authors: Robert S
authors: RS
authors: Svatek
authors: Department of Epidemiology and Biostatistics, UTHSCSA, San Antonio, Texas.
authors: Jonathan A
authors: JA
authors: Gelfond
authors: Department of Medicine, UTHSCSA, San Antonio, Texas.
authors: Aijie
authors: A
authors: Liu
authors: Department of Medicine, UTHSCSA, San Antonio, Texas.
authors: Vincent
authors: V
authors: Hurez
authors: Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio (UTHSCSA), San Antonio, Texas. Department of Medicine, UTHSCSA, San Antonio, Texas. Cancer Therapy & Research Center, UTHSCSA, San Antonio, Texas. Barshop Institute for Longevity and Aging Studies, UTHSCSA, San Antonio, Texas. curielt@uthscsa.edu.
authors: Tyler J
authors: TJ
authors: Curiel
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement; D054357:Chemokine CXCL10 / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D054367:Receptors, CXCR3 / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000517:prevention & control*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000276:Adjuvants, Immunologic; D054357:Chemokine CXCL10; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054367:Receptors, CXCR3; D015127:9,10-Dimethyl-1,2-benzanthracene; D007371:Interferon-gamma; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus