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

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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

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Phosphatidylinositol 3-Kinases
T-Lymphocytes
Aptitude
Neoplasms
Protein Isoforms
Adoptive Transfer
Therapeutics
Phenotype
Granzymes
Subunit Vaccines
Inhibition (Psychology)
Neoplasm Antigens
Cell- and Tissue-Based Therapy
Immunotherapy
Cell Differentiation
Immunity
Vaccines
Cytokines

Keywords

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

Cite this

Enhanced therapeutic efficacy and memory of tumor specific CD8 T cells by ex-vivo PI3K-δ inhibition. / Abu-Eid, Rasha; Ahmad, Shamim; Lin, Yuan; Webb, Mason; Berrong, Zuzana; Shrimali, Rajeev; Kumai, Takumi; Ananth, Sudha; Rodriguez, Paulo C.; Celis, Esteban; Janik, John; Mkrtichyan, Mikayel; Khleif, Samir N.

In: Cancer Research, Vol. 77, No. 15, 08.2017, p. 4135-4145.

Research output: Contribution to journalArticle

Abu-Eid, R, Ahmad, S, Lin, Y, Webb, M, Berrong, Z, Shrimali, R, Kumai, T, Ananth, S, Rodriguez, PC, Celis, E, Janik, J, Mkrtichyan, M & Khleif, SN 2017, 'Enhanced therapeutic efficacy and memory of tumor specific CD8 T cells by ex-vivo PI3K-δ inhibition', Cancer Research, vol. 77, no. 15, pp. 4135-4145. https://doi.org/10.1158/0008-5472.CAN-16-1925
Abu-Eid, Rasha ; Ahmad, Shamim ; Lin, Yuan ; Webb, Mason ; Berrong, Zuzana ; Shrimali, Rajeev ; Kumai, Takumi ; Ananth, Sudha ; Rodriguez, Paulo C. ; Celis, Esteban ; Janik, John ; Mkrtichyan, Mikayel ; Khleif, Samir N. / Enhanced therapeutic efficacy and memory of tumor specific CD8 T cells by ex-vivo PI3K-δ inhibition. In: Cancer Research. 2017 ; Vol. 77, No. 15. pp. 4135-4145.
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