Metabolic reprogramming of antitumor T cells for optimal adoptive immunotherapy

2021 Fiscal Year Annual Research Report

• Project/Area Number: 20K22793
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: 呉 智聞 愛知県がんセンター(研究所), 腫瘍免疫応答研究分野, リサーチレジデント (80883983)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: adoptive immunotherapy / CAR-T / dorsomorphin / AMPK

Outline of Annual Research Achievements

We have explored metabolic targets associated with T cell functions. Dorsomorphin(DM), an inhibitor of the AMPK pathway, helped to maintain CD8+ T cells with a young memory phenotype with repeated antigen exposures. DM-treated T cells showed reduced levels of pAkt and pAMPK. DM-treated T cells showed enhanced persistence compared with the control in NSG mice. The effect of genetic knockout and dominant-negative mutant modification of AMPK subunit (PRKAA1) in CAR-T cells is consistent with the results in vitro. qPCR results show the DM group has an enhanced expression on SELL, TCF7, and IL7R genes and suppressed expression on PDCD1, LAG3, and HAVCR2 genes.
We considered that the inhibition of the metabolic pathway in T cells can enhance their durable effector functions and survival capacity.