PD-1Hi CAR-T cells provide superior protection against solid tumors
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1187850/full |
| _version_ | 1797804550263930880 |
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| author | Cooper J. Sailer Cooper J. Sailer Yeonsun Hong Ankit Dahal Allison T. Ryan Sana Mir Scott A. Gerber Patrick M. Reagan Minsoo Kim |
| author_facet | Cooper J. Sailer Cooper J. Sailer Yeonsun Hong Ankit Dahal Allison T. Ryan Sana Mir Scott A. Gerber Patrick M. Reagan Minsoo Kim |
| author_sort | Cooper J. Sailer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T05:38:52Z |
| format | Article |
| id | doaj.art-b1273da7a6c9425a94ada34badec2d9e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T05:38:52Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b1273da7a6c9425a94ada34badec2d9e2023-06-14T05:06:25ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-06-011410.3389/fimmu.2023.11878501187850PD-1Hi CAR-T cells provide superior protection against solid tumorsCooper J. Sailer0Cooper J. Sailer1Yeonsun Hong2Ankit Dahal3Allison T. Ryan4Sana Mir5Scott A. Gerber6Patrick M. Reagan7Minsoo Kim8Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY, United StatesDepartment of Pathology, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY, United StatesDepartment of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY, United StatesDepartment of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY, United StatesDepartment of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY, United StatesDepartment of Surgery, University of Rochester, Rochester, NY, United StatesDepartment of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY, United StatesChimeric 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1187850/fullcar-tPD-1immune checkpoint blockadeT cell migrationcancer immune cell therapy |
| spellingShingle | Cooper J. Sailer Cooper J. Sailer Yeonsun Hong Ankit Dahal Allison T. Ryan Sana Mir Scott A. Gerber Patrick M. Reagan Minsoo Kim PD-1Hi CAR-T cells provide superior protection against solid tumors Frontiers in Immunology car-t PD-1 immune checkpoint blockade T cell migration cancer immune cell therapy |
| title | PD-1Hi CAR-T cells provide superior protection against solid tumors |
| title_full | PD-1Hi CAR-T cells provide superior protection against solid tumors |
| title_fullStr | PD-1Hi CAR-T cells provide superior protection against solid tumors |
| title_full_unstemmed | PD-1Hi CAR-T cells provide superior protection against solid tumors |
| title_short | PD-1Hi CAR-T cells provide superior protection against solid tumors |
| title_sort | pd 1hi car t cells provide superior protection against solid tumors |
| topic | car-t PD-1 immune checkpoint blockade T cell migration cancer immune cell therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1187850/full |
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