Modulation of T cell phenotype for the design of effective T cell-based cancer therapies 3306

Abstract Description Adoptive cell therapy (ACT) utilizes a patient’s immune cells to effectively target tumor cells by enhancing their function. However, its success can be limited by insufficient immune cell numbers or highly differentiated states that lead to exhaustion. This study aims to improve ACT by manipulating cell culture conditions to achieve optimal T cell phenotypes associated with durable anti-tumor responses. We have previously demonstrated that reducing T cell receptor (TCR) strength produces T cells with a low differentiated phenotype, enabling them to respond vigorously, self-renew, and persist. Additionally, we have found that STING agonists can enhance low-affinity (but not high-affinity) CD8 T cell responses in the context of infection. Therefore, we have explored the use of STING agonists to influence T cell phenotypes based on the strength of antigenic signals.We hypothesized that combining weaker TCR stimulation with STING agonists would yield ideal T cell phenotypes for ACT. Using CD8 T cells specific to a melanoma antigen, we assessed outcomes through multiparameter spectral cytometry to determine the frequencies of tumor-specific CD8 T cells at various differentiation stages linked to favorable anti-tumor responses. Our data suggest that specific combinations of TCR and STING stimulation generate T cell subsets with phenotypes associated with improved prognosis. Funding Sources Ellis Fischel Pilot Grants NCI 1U01CA244314NIH NIAD R56 AI110420 NIH Post-baccalaureate Research Education Program (PREP) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)