Description

Th17 cells are refractory to senescence retaining robust antitumor activity after long-term ex vivo expansion

Jacob S. Bowers^1,2,3*, Michelle H. Nelson^1,2,3, Kinga Majchrzak^1,2,3, Stefanie R. Bailey^1,2,3, Baerbel Rohrer^4,5, Andrew D.M. Kaiser⁶, Carl Atkinson¹, Luca Gattinoni⁷, Chrystal M. Paulos^1,2,3

¹Department of Microbiology and Immunology, Medical University of South Carolina, ²Department of Dermatology, Medical University of South Carolina, ³Department of Surgery, Medical University of South Carolina, ⁴Department of Ophthalmology, Medical University of South Carolina, ⁵Ralph H. Johnson VA Medical Center, ⁶Miltenyi Biotec, ⁷Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH)

*Corresponding Author

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 (REP) produce sufficient numbers ofCD8⁺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 REP to expand 5,000-fold over three 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 one week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after two or three weeks of expansion, while the cell-yield obtained after one-week expansion was insufficient. Long-term expanded Th17 cells also protected mice from tumor re-challenge including lung metastasis. Importantly, two week expanded human CAR⁺Th17 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 long duration due to their resistance to senescence.