Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors
In-Young Jung, Estela Noguera-Ortega, Robert L. Bartoszek, Sierra M. Collins, Erik F. Williams, Megan M. Davis, Julie K. Jadlowsky, Gabriela Plesa, Donald L. Siegel, Anne Chew, Bruce L. Levine, Shelley L. Berger, Edmund K. Moon, Steven Μ. Albelda, Joseph A. Fraietta
Abstract
Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malignancies, but their effectiveness in non-hematopoietic cancers remains limited. This study proposes enhancing CAR T cell function and localization in solid tumors by modifying the epigenome governing tissue-residency adaptation and early memory differentiation. We identify that a key factor in human tissue-resident memory CAR T cell (CAR-T RM ) formation is activation in the presence of the pleotropic cytokine, transforming growth factor β (TGF-β), which enforces a core program of both "stemness" and sustained tissue residency by mediating chromatin remodeling and concurrent transcriptional changes. This approach leads to a practical and clinically actionable in vitro production method for engineering peripheral blood T cells into a large number of "stem-like" CAR-T RM cells resistant to tumor-associated dysfunction, possessing an enhanced ability to accumulate in situ and rapidly eliminate cancer cells for more effective immunotherapy.