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

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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

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T-Lymphocyte Subsets
Phosphatidylinositol 3-Kinases
Immunotherapy
Neoplasms
T-Lymphocytes
Protein Isoforms
Cancer Vaccines
Tumor Microenvironment
Regulatory T-Lymphocytes
T-Cell Antigen Receptor
Lung Neoplasms
Cell Survival
Vaccines
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Differential PI3Kδ signaling in CD4+ T-cell subsets enables selective targeting of t regulatory cells to enhance cancer immunotherapy. / Ahmad, Shamim; Abu-Eid, Rasha; Shrimali, Rajeev Kumar; Webb, Mason; Verma, Vivek; Doroodchi, Atbin; Berrong, Zuzana; Samara, Raed; Rodriguez, Paulo C.; Mkrtichyan, Mikayel; Khleif, Samir N.

In: Cancer Research, Vol. 77, No. 8, 15.04.2017, p. 1892-1904.

Research output: Contribution to journalArticle

Ahmad, S, Abu-Eid, R, Shrimali, RK, Webb, M, Verma, V, Doroodchi, A, Berrong, Z, Samara, R, Rodriguez, PC, Mkrtichyan, M & Khleif, SN 2017, 'Differential PI3Kδ signaling in CD4+ T-cell subsets enables selective targeting of t regulatory cells to enhance cancer immunotherapy', Cancer Research, vol. 77, no. 8, pp. 1892-1904. https://doi.org/10.1158/0008-5472.CAN-16-1839
Ahmad, Shamim ; Abu-Eid, Rasha ; Shrimali, Rajeev Kumar ; Webb, Mason ; Verma, Vivek ; Doroodchi, Atbin ; Berrong, Zuzana ; Samara, Raed ; Rodriguez, Paulo C. ; Mkrtichyan, Mikayel ; Khleif, Samir N. / Differential PI3Kδ signaling in CD4+ T-cell subsets enables selective targeting of t regulatory cells to enhance cancer immunotherapy. In: Cancer Research. 2017 ; Vol. 77, No. 8. pp. 1892-1904.
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