CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy
Despite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Cancer Biology & Therapy |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15384047.2024.2398801 |
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| author | Trevor R. Baybutt Ariana A. Entezari Adi Caspi Ross E. Staudt Robert D. Carlson Scott A. Waldman Adam E. Snook |
| author_facet | Trevor R. Baybutt Ariana A. Entezari Adi Caspi Ross E. Staudt Robert D. Carlson Scott A. Waldman Adam E. Snook |
| author_sort | Trevor R. Baybutt |
| collection | DOAJ |
| description | Despite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges remains focused on the intracellular signaling and antigen-binding domains. In contrast, the flexible hinge and transmembrane domains have been commoditized and are the least studied components of the CAR. Here, we compared the hinge and transmembrane domains derived from either the CD8ɑ or CD28 molecule in identical GUCY2C-targeted third-generation designs for colorectal cancer. While these structural domains do not contribute to differences in antigen-independent contexts, such as CAR expression and differentiation and exhaustion phenotypes, the CD8ɑ structural domain CAR has a greater affinity for GUCY2C. This results in increased production of inflammatory cytokines and granzyme B, improved cytolytic effector function with low antigen-expressing tumor cells, and robust anti-tumor efficacy in vivo compared with the CD28 structural domain CAR. This suggests that CD8α structural domains should be considered in the design of all CARs for the generation of high-affinity CARs and optimally effective CAR-T cells in solid tumor immunotherapy. |
| format | Article |
| id | doaj-art-c3e69bce597b487bb55e73a30b89f87f |
| institution | OA Journals |
| issn | 1538-4047 1555-8576 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj-art-c3e69bce597b487bb55e73a30b89f87f2025-08-20T01:58:48ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762024-12-0125110.1080/15384047.2024.2398801CD8α Structural Domains Enhance GUCY2C CAR-T Cell EfficacyTrevor R. Baybutt0Ariana A. Entezari1Adi Caspi2Ross E. Staudt3Robert D. Carlson4Scott A. Waldman5Adam E. Snook6Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USADespite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges remains focused on the intracellular signaling and antigen-binding domains. In contrast, the flexible hinge and transmembrane domains have been commoditized and are the least studied components of the CAR. Here, we compared the hinge and transmembrane domains derived from either the CD8ɑ or CD28 molecule in identical GUCY2C-targeted third-generation designs for colorectal cancer. While these structural domains do not contribute to differences in antigen-independent contexts, such as CAR expression and differentiation and exhaustion phenotypes, the CD8ɑ structural domain CAR has a greater affinity for GUCY2C. This results in increased production of inflammatory cytokines and granzyme B, improved cytolytic effector function with low antigen-expressing tumor cells, and robust anti-tumor efficacy in vivo compared with the CD28 structural domain CAR. This suggests that CD8α structural domains should be considered in the design of all CARs for the generation of high-affinity CARs and optimally effective CAR-T cells in solid tumor immunotherapy.https://www.tandfonline.com/doi/10.1080/15384047.2024.2398801Chimeric antigen receptorCAR-T cell therapyGUCY2Ccolorectal cancer |
| spellingShingle | Trevor R. Baybutt Ariana A. Entezari Adi Caspi Ross E. Staudt Robert D. Carlson Scott A. Waldman Adam E. Snook CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy Cancer Biology & Therapy Chimeric antigen receptor CAR-T cell therapy GUCY2C colorectal cancer |
| title | CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy |
| title_full | CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy |
| title_fullStr | CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy |
| title_full_unstemmed | CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy |
| title_short | CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy |
| title_sort | cd8α structural domains enhance gucy2c car t cell efficacy |
| topic | Chimeric antigen receptor CAR-T cell therapy GUCY2C colorectal cancer |
| url | https://www.tandfonline.com/doi/10.1080/15384047.2024.2398801 |
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