Herpes virus entry mediator costimulation signaling enhances CAR-T cell efficacy against solid tumors through metabolic reprogramming

  • Cancer Immunol Res. 2023 Jan 23;CIR-22-0531. doi: 10.1158/2326-6066.CIR-22-0531.
Shishuo Sun  1 ,  Chao Huang  2 ,  Mengmeng Lu  2 ,  Heng Xu  2 ,  Yifan Yuan  2 ,  Wanxin Zhao  2 ,  Xiaolei Hu  2 ,  Bixi Wang  2 ,  Wei Zhang  2 ,  Xiaoge Gao  3 ,  Junnian Zheng  4 ,  Lishan Su  5 ,  Qing Zhang  2
Affiliations
  • 1. Xuzhou Medical University, China.
  • 2. Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3. Cancer Institute, Xuzhou, China.
  • 4. Xuzhou Medical University, Xuzhou, China.
  • 5. University of Maryland School of Medicine, Baltimore, Maryland, United States.
PMID: 36689620 DOI: 10.1158/2326-6066.CIR-22-0531
Abstract

Costimulatory domains (CSD) of 4-1BB and CD28 are most widely used in chimeric antigen receptor-engineered T (CAR-T) cells. These CAR-T cells have shown encouraging efficacy in the treatment of hematologic malignancies but have limited efficacy in solid tumors. The herpes virus entry mediator (HVEM) is a costimulatory molecule with a novel downstream signaling pathway. In response to target cells, CAR-T cells with a HVEM CSD (HVEM-CAR-T) displayed more robust cytokine release and cytotoxicity than 4-1BB- or CD28-CAR-T in vitro. Furthermore, HVEM-CAR-T showed superior therapeutic efficacy in several mouse tumor models. Mechanistically, the HVEM CSD endowed CAR-T cells with attenuated exhaustion, improved function and persistence, and enhanced metabolic activities in tumor tissue compared with 4-1BB- or CD28-based CAR-T cells. These studies establish that the HVEM CSD has the potential to improve the therapeutic efficacy of CAR-T cells against solid tumors.

Products
Inhibitors & Agonists
Other Products