Activating and propagating polyclonal gamma delta T cells with broad specificity for malignancies.

ABSTRACT: To activate and propagate populations of ?? T cells expressing polyclonal repertoire of ? and ? T-cell receptor (TCR) chains for adoptive immunotherapy of cancer, which has yet to be achieved.Clinical-grade artificial antigen-presenting cells (aAPC) derived from K562 tumor cells were used as irradiated feeders to activate and expand human ?? T cells to clinical scale. These cells were tested for proliferation, TCR expression, memory phenotype, cytokine secretion, and tumor killing.?? T-cell proliferation was dependent upon CD137L expression on aAPC and addition of exogenous IL2 and IL21. Propagated ?? T cells were polyclonal as they expressed TRDV1, TRDV2-2, TRDV3, TRDV5, TRDV7, and TRDV8 with TRGV2, TRGV3F, TRGV7, TRGV8, TRGV9*A1, TRGV10*A1, and TRGV11 TCR chains. IFN? production by V?1, V?2, and V?1(neg)V?2(neg) subsets was inhibited by pan-TCR?? antibody when added to cocultures of polyclonal ?? T cells and tumor cell lines. Polyclonal ?? T cells killed acute and chronic leukemia, colon, pancreatic, and ovarian cancer cell lines, but not healthy autologous or allogeneic normal B cells. Blocking antibodies demonstrated that polyclonal ?? T cells mediated tumor cell lysis through combination of DNAM1, NKG2D, and TCR??. The adoptive transfer of activated and propagated ?? T cells expressing polyclonal versus defined V? TCR chains imparted a hierarchy (polyclonal>V?1>V?1(neg)V?2(neg)>V?2) of survival of mice with ovarian cancer xenografts.Polyclonal ?? T cells can be activated and propagated with clinical-grade aAPCs and demonstrate broad antitumor activities, which will facilitate the implementation of ?? T-cell cancer immunotherapies in humans.

SUBMITTER: Deniger DC 

PROVIDER: S-EPMC4233015 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature