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 Kumar Shrimali, Takumi Kumai, Sudha Ananth, Paulo C. Rodriguez, Esteban Celis, John Edward Janik, Mikayel Mkrtichyan, Samir N. Khleif

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Inhibition of specific Akt isoforms in CD8þ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating antitumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8þ T-cell differentiation and assessed the potential use of PI3K isoform–specific inhibitors to favorably condition CD8þ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen–specific CD8þ T cells was assessed in the presence of PI3K-a, -b, or -d inhibitors. Inhibition of PI3K-d, but not PI3K-a or PI3K-b, delayed terminal differentiation of CD8þ 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 ex vivo PI3K-d inhibition in CD8þ T cells destined for adoptive transfer, enhancing their survival and also the antitumor 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 CD8þ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies.

Original languageEnglish (US)
Pages (from-to)4135-4145
Number of pages11
JournalCancer Research
Volume77
Issue number15
DOIs
Publication statusPublished - Aug 1 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Abu Eid, R., Ahmad, S., Lin, Y., Webb, M., Berrong, Z., Shrimali, R. K., ... Khleif, S. N. (2017). Enhanced therapeutic efficacy and memory of tumor-specific CD8 T cells by ex vivo PI3K-δ inhibition. Cancer Research, 77(15), 4135-4145. https://doi.org/10.1158/0008-5472.CAN-16-1925