Differential PI3Kδ signaling in CD4+ T-cell subsets enables selective targeting of t regulatory cells to enhance cancer immunotherapy

Shamim Ahmad, Rasha Abu-Eid, Rajeev Kumar Shrimali, Mason Webb, Vivek Verma, Atbin Doroodchi, Zuzana Berrong, Raed Samara, Paulo C. Rodriguez, Mikayel Mkrtichyan, Samir N. Khleif

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

To modulate T-cell function for cancer therapy, one challenge is to selectively attenuate regulatory but not conventional CD4+ T-cell subsets [regulatory T cell (Treg) and conventional T cell (Tconv)]. In this study, we show how a functional dichotomy in Class IA PI3K isoforms in these two subsets of CD4+ T cells can be exploited to target Treg while leaving Tconv intact. Studies employing isoform-specific PI3K inhibitors and a PI3Kδ-deficient mouse strain revealed that PI3Kα and PI3Kβ were functionally redundant with PI3Kδ in Tconv. Conversely, PI3Kδ was functionally critical in Treg, acting there to control T-cell receptor signaling, cell proliferation, and survival. Notably, in a murine model of lung cancer, coadministration of a PI3Kδ-specific inhibitor with a tumor-specific vaccine decreased numbers of suppressive Treg and increased numbers of vaccine-induced CD8 T cells within the tumor microenvironment, eliciting potent antitumor efficacy. Overall, our results offer a mechanistic rationale to employ PI3Kδ inhibitors to selectively target Treg and improve cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)1892-1904
Number of pages13
JournalCancer Research
Volume77
Issue number8
DOIs
StatePublished - Apr 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ahmad, S., Abu-Eid, R., Shrimali, R. K., Webb, M., Verma, V., Doroodchi, A., Berrong, Z., Samara, R., Rodriguez, P. C., Mkrtichyan, M., & Khleif, S. N. (2017). Differential PI3Kδ signaling in CD4+ T-cell subsets enables selective targeting of t regulatory cells to enhance cancer immunotherapy. Cancer Research, 77(8), 1892-1904. https://doi.org/10.1158/0008-5472.CAN-16-1839