TY - JOUR
T1 - Differential PI3Kδ signaling in CD4+ T-cell subsets enables selective targeting of t regulatory cells to enhance cancer immunotherapy
AU - Ahmad, Shamim
AU - Abu-Eid, Rasha
AU - Shrimali, Rajeev Kumar
AU - Webb, Mason
AU - Verma, Vivek
AU - Doroodchi, Atbin
AU - Berrong, Zuzana
AU - Samara, Raed
AU - Rodriguez, Paulo C.
AU - Mkrtichyan, Mikayel
AU - Khleif, Samir N.
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/4/15
Y1 - 2017/4/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-16-1839
DO - 10.1158/0008-5472.CAN-16-1839
M3 - Article
C2 - 28108509
AN - SCOPUS:85018859119
SN - 0008-5472
VL - 77
SP - 1892
EP - 1904
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -