Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15 complexes mediate proliferation of high-avidity central memory CD8(+) T cells for adoptive immunotherapy of cancer and infections Journal Article

   

Authors:	Hasan, A. N.; Selvakumar, A.; Shabrova, E.; Liu, X. R.; Afridi, F.; Heller, G.; Riviere, I.; Sadelain, M.; Dupont, B.; O'Reilly, R. J.
Article Title:	Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15 complexes mediate proliferation of high-avidity central memory CD8(+) T cells for adoptive immunotherapy of cancer and infections
Abstract:	The lack of persistence of infused T cells is a principal limitation of adoptive immunotherapy in man. Interleukin (IL)-15 can sustain memory T cell expansion when presented in complex with IL-15Rα (15Rα/15). We developed a novel in-vitro system for generation of stable 15Rα/15 complexes. Immunologically quantifiable amounts of IL-15 were obtained when both IL-15Rα and IL-15 genes were co-transduced in NIH 3T3 fibroblast-based artificial antigen-presenting cells expressing human leucocyte antigen (HLA) A:0201, β2 microglobulin, CD80, CD58 and CD54 [A2-artificial antigen presenting cell (AAPC)] and a murine pro-B cell line (Baf-3) (A2-AAPC15Rα/15and Baf-315Rα/15). Transduction of cells with IL-15 alone resulted in only transient expression of IL-15, with minimal amounts of immunologically detectable IL-15. In comparison, cells transduced with IL-15Rα alone (A2-AAPCRα) demonstrated stable expression of IL-15Rα; however, when loaded with soluble IL-15 (sIL-15), these cells sequestered 15Rα/15 intracellularly and also demonstrated minimal amounts of IL-15. Human T cells stimulated in vitro against a viral antigen (CMVpp65) in the presence of 15Rα/15 generated superior yields of high-avidity CMVpp65 epitope-specific T cells [cytomegalovirus-cytotoxic T lymphocytes (CMV-CTLs)] responding to ≤ 10− 13 M peptide concentrations, and lysing targets cells at lower effector : target ratios (1 : 10 and 1 : 100), where sIL-15, sIL-2 or sIL-7 CMV-CTLs demonstrated minimal or no activity. Both soluble and surface presented 15Rα/15, but not sIL-15, sustained in-vitro expansion of CD62L+ and CCR7+ central memory phenotype CMV-CTLs (TCM). 15Rα/15 complexes represent a potent adjuvant for augmenting the efficacy of adoptive immunotherapy. Such cell-bound or soluble 15Rα/15 complexes could be developed for use in combination immunotherapy approaches. © 2016 British Society for Immunology
Keywords:	cancer immunotherapy; cytokine; immunomodulation; adoptive immunotherapy; immune adjuvant; t cell memory
Journal Title:	Clinical and Experimental Immunology
Volume:	186
Issue:	2
ISSN:	0009-9104
Publisher:	British Society for Immunology
Date Published:	2016-11-01
Start Page:	249
End Page:	265
Language:	English
DOI:	10.1111/cei.12816
PUBMED:	27227483
PROVIDER:	scopus
PMCID:	PMC5054569
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-84990245224&partnerID=40&md5=a32b13b1c9b2fc2ccdaf7fd5ccf5f570
Notes:	Article -- Export Date: 2 November 2016 -- Source: Scopus