| First Author | Ahmad S | Year | 2017 |
| Journal | Cancer Res | Volume | 77 |
| Issue | 8 | Pages | 1892-1904 |
| PubMed ID | 28108509 | Mgi Jnum | J:241026 |
| Mgi Id | MGI:5897514 | Doi | 10.1158/0008-5472.CAN-16-1839 |
| Citation | Ahmad S, et al. (2017) Differential PI3Kdelta Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy. Cancer Res 77(8):1892-1904 |
| abstractText | 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 PI3Kdelta-deficient mouse strain revealed that PI3Kalpha and PI3Kbeta were functionally redundant with PI3Kdelta in Tconv. Conversely, PI3Kdelta 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 PI3Kdelta-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 PI3Kdelta inhibitors to selectively target Treg and improve cancer immunotherapy. Cancer Res; 77(8); 1892-904. (c)2017 AACR. |
