Selective Refueling of Car T Cells Using ADA1 and CD26 Boosts Antitumor Immunity

Authors

Yue Hu
Abhijit Sarkar
Kevin Song
Sara Michael
Magnus Hook
Ruoning Wang
Andras Heczey
Xiaotong Song

Publication Date

5-21-2024

Journal

Cell Reports Medicine

Abstract

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor β1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor cell feeding. In mouse models of hepatocellular carcinoma and non-small cell lung cancer, metabolically refueled CAR T cells exhibit superior tumor reduction compared to unmodified CAR T cells. Overall, our study highlights the potential of selective inosine refueling to enhance CAR T therapy efficacy against solid tumors.

Keywords

CAR T cell, ADA, ADA1 autocrine secretion, T cell engager, anti-CD3 scFv, CD26, inosine, adenosine, solid tumor, metabolic reprogramming

Comments

Supplementary Materials

PMID: 38688275