title: Differential PI3Kδ Signaling in CD4+T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy.
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.Cancer Res; 77(8); 1892-904. ©2017 AACR.
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Shamim
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|University of Aberdeen Dental School, Foresterhill, Aberdeen, Scotland, United Kingdom.
authors.forename: Rasha
authors.initials: R
authors.lastname: Abu-Eid
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.|Peloton Therapeutics, Dallas, Texas.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Shrimali
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Mason
authors.initials: M
authors.lastname: Webb
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Vivek
authors.initials: V
authors.lastname: Verma
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Atbin
authors.initials: A
authors.lastname: Doroodchi
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Berrong
authors.affiliation: R&D Project Management Department, Qiagen, Frederick, Maryland.
authors.forename: Raed
authors.initials: R
authors.lastname: Samara
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia.
authors.forename: Mikayel
authors.initials: M
authors.lastname: Mkrtichyan
authors.affiliation: Georgia Cancer Center, Augusta University, Augusta, Georgia. skhleif@augusta.edu.
authors.forename: Samir N
authors.initials: SN
authors.lastname: Khleif
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007167:Immunotherapy / Q000379:methods; D007527:Isoenzymes; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology* / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib