title: IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo.
abstract: Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). Tumor antigen-sensitized DLN lymphocytes from BALB/c mice with 10-day 4T1 mammary carcinomas were harvested, activated with B/I, and expanded in culture with either interleukin-2 (IL-2) or IL-7 + IL-15. Cell yields, proliferation, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for antitumor activity against established 4T1 mammary carcinomas after inoculation of tumor cells subcutaneously (s.c.). IL-7/15 resulted in much faster and more prolonged proliferation of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately 5-10-fold greater yields of viable cells. Culture in IL-7/15 yielded higher proportions of CD8(+) T cells and a higher proportion of cells with a central memory phenotype. T cells grown in IL-2 had higher interferon-gamma (IFN-gamma) release responses to tumor antigen than cells grown in IL-7/15. Adoptive transfer of B/I-activated T cells grown in IL-7/15 demonstrated much greater efficacy against 4T1 tumors in vivo. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in AIT of cancer.
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University's Medical College of Virginia, Richmond, VA, USA. estherhyunwoocha@gmail.com
authors.forename: Esther
authors.initials: E
authors.lastname: Cha
authors.forename: Laura
authors.initials: L
authors.lastname: Graham
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.forename: Harry D
authors.initials: HD
authors.lastname: Bear
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D054713:Bryostatins / Q000494:pharmacology; D002277:Carcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D047368:Tumor Burden
chemical_list: D000951:Antigens, Neoplasm; D054713:Bryostatins; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D011994:Recombinant Proteins; C046785:bryostatin 1; D015759:Ionomycin; D007371:Interferon-gamma