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.
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.
Cha
Esther
E
Department of Physiology and Biophysics, Virginia Commonwealth University's Medical College of Virginia, Richmond, VA, USA. estherhyunwoocha@gmail.com
Graham
Laura
L
Manjili
Masoud H
MH
Bear
Harry D
HD
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
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