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PD-1Hi CAR-T cells provide superior protection against solid tumors.
- Source :
- Frontiers in Immunology; 2023, p1-14, 14p
- Publication Year :
- 2023
-
Abstract
- Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising treatment option for several hematologic cancers. However, efforts to achieve the same level of therapeutic success in solid tumors have largely failed mainly due to CAR-T cell exhaustion and poor persistence at the tumor site. Although immunosuppression mediated by augmented programmed cell death protein-1 (PD-1) expression has been proposed to cause CAR-T cell hypofunction and limited clinical efficacy, little is known about the underlying mechanisms and immunological consequences of PD-1 expression on CAR-T cells. With flow cytometry analyses and in vitro and in vivo anti-cancer T cell function assays, we found that both manufactured murine and human CAR-T cell products displayed phenotypic signs of T cell exhaustion and heterogeneous expression levels of PD- 1. Unexpectedly, PD-1high CAR-T cells outperformed PD-1low CAR-T cells in multiple T cell functions both in vitro and in vivo. Despite the achievement of superior persistence at the tumor site in vivo, adoptive transfer of PD-1high CAR-T cells alone failed to control tumor growth. Instead, a PD-1 blockade combination therapy significantly delayed tumor progression in mice infused with PD-1high CAR-T cells. Therefore, our data demonstrate that robust T cell activation during the ex vivo CAR-T cell manufacturing process generates a PD-1high CAR-T cell subset with improved persistence and enhanced anti-cancer functions. However, these cells may be vulnerable to the immunosuppressive microenvironment and require combination with PD-1 inhibition to maximize therapeutic functions in solid tumors. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 16643224
- Database :
- Complementary Index
- Journal :
- Frontiers in Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 164644382
- Full Text :
- https://doi.org/10.3389/fimmu.2023.1187850