T cell co-stimulation reprograms the metabolic fitness of highly differentiated CD8+ T cells for improved adoptive T–cell therapy

Abstract

Abstract Adoptive T cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) can result in durable complete cancer remission in select patients with metastatic melanoma. These clinical responses have strongly correlated with the ability of the transferred cells to engraft and persist in these patients. Preclinical murine studies have further supported that T cells with superior anti-tumor efficacy have higher proliferative capacity, reduced AICD and enhanced in vivo persistence. Thus, in an effort to further improve ACT, we sought to exploit ex vivo 4-1BB co-stimulation to generate T cells with enhanced in vivo anti-tumor activity. We used an artificial APCs genetically engineered to express 4-1BBL to provide ex-vivo 4-1BB co-stimulation to human tumor specific CD8+ T cells. Our results demonstrate that ex-vivo 4-1BBL co-stimulation enhanced proliferative capacity and reduced AICD of the CD8+ T cells without loss of functional tumor avidity. Mechanistically, 4-1BB co-stimulation demonstrated enhanced glycolysis (ECAR) and mitochondrial respiration (OXPHOS) further suggested that 4-1BB co-stimulation could induce significant reprogramming of the bioenergetic pathways used by highly differentiated T cells. The 4-1BB co-stimulation further restored the ability of the highly differentiated T cells to persist and survive after adoptive transfer in NSG mice and resulted in improved survival of established tumor bearing NSG mice. These findings shed light on a fundamental role of 4-1BB co-stimulation and further suggest a practical approach to reprogram the metabolic fitness of highly differentiated T cells for adoptive immunotherapy