Enhanced therapeutic efficacy and memory of tumor specific CD8 T cells by ex-vivo PI3K-δ inhibition

Rasha Abu-Eid, Shamim Ahmad, Yuan Lin, Mason Webb, Zuzana Berrong, Rajeev Shrimali, Takumi Kumai, Sudha Ananth, Paulo C. Rodriguez, Esteban Celis, John Janik, Mikayel Mkrtichyan, Samir N. Khleif

Research output: Contribution to journalArticle

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Abstract

Inhibition of specific Akt isoforms in CD8+ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating anti-tumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8+ T cell differentiation and assessed the potential use of PI3K isoform-specific inhibitors to favorably condition CD8+ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen specific CD8+ T cells was assessed in the presence of PI3K-α, -β, or -δ inhibitors. Inhibition of PI3K-δ, but not PI3K-α or PI3K-β, delayed terminal differentiation of CD8+ T cells and maintained the memory phenotype, thus enhancing their proliferative ability and survival while maintaining their cytokine and granzyme B production ability. This effect was preserved in vivo after of ex vivo PI3K-δ inhibition in CD8+ T cells destined for adoptive transfer, enhancing their survival and also the anti-tumor therapeutic activity of a tumor-specific peptide vaccine. Our results outline a mechanism by which inhibitions of a single PI3K isoform can enhance the proliferative potential, function and survival of CD8+ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies.

Original languageEnglish
Pages (from-to)4135-4145
Number of pages11
JournalCancer Research
Volume77
Issue number15
Early online date14 Jun 2017
DOIs
Publication statusPublished - Aug 2017

Keywords

  • memory
  • Akt
  • PI3K
  • proliferation
  • CD8+ T-cells
  • adoptive cell transfer

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