Differential PI3Kδ Signaling in CD4 + T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-04, Vol.77 (8), p.1892-1904
• Main Authors: Ahmad, Shamim, Abu-Eid, Rasha, Shrimali, Rajeev, Webb, Mason, Verma, Vivek, Doroodchi, Atbin, Berrong, Zuzana, Samara, Raed, Rodriguez, Paulo C, Mkrtichyan, Mikayel, Khleif, Samir N
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Animal models; Animals; Antitumor activity; Cancer; Cancer immunotherapy; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; CD4 antigen; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell proliferation; Cell survival; Drug Synergism; Enzyme Inhibitors - pharmacology; Female; Immunoregulation; Immunotherapy; Immunotherapy - methods; Inhibitors; Isoenzymes; Isoforms; Lung cancer; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms, Experimental - enzymology; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - immunology; Purines - pharmacology; Quinazolinones - pharmacology; Signal Transduction - immunology; T cell receptors; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - enzymology; T-Lymphocytes, Regulatory - immunology; Vaccines
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-1839

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. .