title: Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion.
abstract: Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8+T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4+T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo. Three-week-expanded Th17 cells eliminated melanoma as effectively as Th17 cells expanded for 1 week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after 2 or 3 weeks of expansion, while the cell yield obtained after 1-week expansion was insufficient. Long-term-expanded Th17 cells also protected mice from tumor rechallenge including lung metastasis. Importantly, 2-week-expanded human chimeric antigen receptor-positive (CAR+) Th17 cells also retained their ability to regress human mesothelioma, while CAR+Th1 cells did not. Our results indicate that tumor-reactive Th17 cells are an effective cell therapy for cancer, remaining uncompromised when expanded for a long duration owing to their resistance to senescence.
authors.affiliation: Department of Microbiology and Immunology.|Department of Dermatology.|Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Bowers
authors.affiliation: Department of Microbiology and Immunology.|Department of Dermatology.|Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Nelson
authors.affiliation: Department of Microbiology and Immunology.|Department of Dermatology.|Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.|Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Majchrzak
authors.affiliation: Department of Microbiology and Immunology.|Department of Dermatology.|Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Stefanie R
authors.initials: SR
authors.lastname: Bailey
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, USA.|Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA.
authors.forename: Baerbel
authors.initials: B
authors.lastname: Rohrer
authors.affiliation: Center for Cancer Research.
authors.forename: Andrew Dm
authors.initials: AD
authors.lastname: Kaiser
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.affiliation: Department of Microbiology and Immunology.|Department of Dermatology.|Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000276:immunology* / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D008654:Mesothelioma / Q000276:immunology* / Q000628:therapy; D000086002:Mesothelioma, Malignant; D051379:Mice; D008810:Mice, Inbred C57BL; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology*