title: Reducing CD73 expression by IL1β-Programmed Th17 cells improves immunotherapeutic control of tumors.
abstract: T cells of the T helper (Th)17 subset offer promise in adoptive T-cell therapy for cancer. However, current protocols for ex vivo programming of Th17 cells, which include TGFβ exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression. Here, we report that ATP-mediated suppression of IFNγ production by Th17 cells can be overcome by genetic ablation of CD73 or by using IL1β instead of TGFβ to program Th17 cells ex vivo. Th17 cells cultured in IL1β were also highly polyfunctional, expressing high levels of effector molecules and exhibiting superior short-term control of melanoma in mice, despite reduced stem cell-like properties. TGFβ addition at low doses that did not upregulate CD73 expression but induced stemness properties drastically improved the antitumor effects of IL1β-cultured Th17 cells. Effector properties of IL1β-dependent Th17 cells were likely related to their high glycolytic capacity, since ex vivo programming in pyruvate impaired glycolysis and antitumor effects. Overall, we show that including TGFβ in ex vivo cultures used to program Th17 cells blunts their immunotherapeutic potential and demonstrate how this potential can be more fully realized for adoptive T-cell therapy.
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Shilpak
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Thyagarajan
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Pravin
authors.initials: P
authors.lastname: Kesarwani
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Song
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Myroslawa
authors.initials: M
authors.lastname: Soloshchenko
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Jianing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Stefanie R
authors.initials: SR
authors.lastname: Bailey
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Chenthamarkshan
authors.initials: C
authors.lastname: Vasu
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
authors.affiliation: Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. mehrotr@musc.edu.
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
mesh_terms: D015720:5'-Nucleotidase / Q000096:biosynthesis* / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D001081:Apyrase / Q000096:biosynthesis / Q000276:immunology; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016219:Immunotherapy, Adoptive; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; C508585:IL1B protein, human; D053583:Interleukin-1beta; D016212:Transforming Growth Factor beta; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D001081:Apyrase; C067869:CD39 antigen