Ding et al. showed that murine tumor-specific CD4+ T cells transduced with constitutively active STAT5A (CASTAT5) transferred into tumor-bearing mice had a polyfunctional cytokine profile, expanded and amassed in blood and tumors, and regressed large vascularized tumors via host tumor-specific CD8+ T cells. RNAseq and ATACseq analyses showed that CASTAT5 promoted transcriptional and epigenetic changes and a polyfunctional CD4+ T cell signature. Co-transfer of CASTAT5-transduced CD19-CAR murine CD4+ and CD8+ T cells induced optimal tumor regression. CASTAT5-transduced primary human CD4+ T cells had a polyfunctional phenotype.
Contributed by Paula Hochman
ABSTRACT: The presence of polyfunctional CD4(+) T cells is often associated with favorable antitumor immunity. We report here that persistent activation of signal transducer and activator of transcription 5 (STAT5) in tumor-specific CD4(+) T cells drives the development of polyfunctional T cells. We showed that ectopic expression of a constitutively active form of murine STAT5A (CASTAT5) enabled tumor-specific CD4(+) T cells to undergo robust expansion, infiltrate tumors vigorously, and elicit antitumor CD8(+) T cell responses in a CD4(+) T cell adoptive transfer model system. Integrated epigenomic and transcriptomic analysis revealed that CASTAT5 induced genome-wide chromatin remodeling in CD4(+) T cells and established a distinct epigenetic and transcriptional landscape. Single-cell RNA sequencing analysis further identified a subset of CASTAT5-transduced CD4(+) T cells with a molecular signature indicative of progenitor polyfunctional T cells. The therapeutic significance of CASTAT5 came from our finding that adoptive transfer of T cells engineered to coexpress CD19-targeting chimeric antigen receptor (CAR) and CASTAT5 gave rise to polyfunctional CD4(+) CAR T cells in a mouse B cell lymphoma model. The optimal therapeutic outcome was obtained when both CD4(+) and CD8(+) CAR T cells were transduced with CASTAT5, indicating that CASTAT5 facilitates productive CD4 help to CD8(+) T cells. Furthermore, we provide evidence that CASTAT5 is functional in primary human CD4(+) T cells, underscoring its potential clinical relevance. Our results implicate STAT5 as a valid candidate for T cell engineering to generate polyfunctional, exhaustion-resistant, and tumor-tropic antitumor CD4(+) T cells to potentiate adoptive T cell therapy for cancer.
Author Info: (1) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. gzhou@augusta.edu zding@augusta.edu hshi@augusta.edu. (2) Georgia Cancer Center, Medica
Author Info: (1) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. gzhou@augusta.edu zding@augusta.edu hshi@augusta.edu. (2) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. gzhou@augusta.edu zding@augusta.edu hshi@augusta.edu. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA. (3) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. (4) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. (5) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. (6) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, China. (7) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. (8) Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. (9) Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA. (10) Division of Biostatistics and Data Science, Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA, USA. (11) University of South Alabama Mitchell Cancer Institute, Mobile, AL, USA. (12) Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA. (13) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. (14) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA. gzhou@augusta.edu zding@augusta.edu hshi@augusta.edu. Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
