Article ; Online: Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis.
Journal for immunotherapy of cancer
2024 Volume 12, Issue 2
Abstract: Background: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity ... ...
| Abstract | Background: Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack of suitable tumor-specific antigens and the immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity and persistence. We hypothesized that targeting the endosialin (CD248) receptor, strongly expressed by tumor-associated pericytes and perivascular cancer-associated fibroblasts, would circumvent these challenges and offer an exciting antigen for CAR-T cell therapy due to the close proximity of target cells to the tumor vasculature, the limited endosialin expression in normal tissues and the lack of phenotype observed in endosialin knockout mice. Methods: We generated endosialin-directed E3K CAR-T cells from three immunocompetent mouse strains, BALB/c, FVB/N and C57BL/6. E3K CAR-T cell composition (CD4 Results: E3K CAR-T cells were active in vitro against both mouse and human endosialin Conclusions: Together these data highlight endosialin as a viable antigen for CAR-T cell therapy and that targeting stromal cells closely associated with the tumor vasculature avoids CAR-T cells having to navigate the harsh immunosuppressive tumor microenvironment. Further, the ability of E3K CAR-T cells to recognize and target both mouse and human endosialin |
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| MeSH term(s) | Humans ; Mice ; Animals ; Pericytes/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Mice, Inbred C57BL ; Neoplasms/metabolism ; T-Lymphocytes/metabolism ; Mice, Knockout ; Tumor Microenvironment ; Antigens, Neoplasm/metabolism ; Antigens, CD/metabolism |
| Chemical Substances | Receptors, Chimeric Antigen ; CD248 protein, human ; Antigens, Neoplasm ; Antigens, CD ; CD248 protein, mouse |
| Language | English |
| Publishing date | 2024-02-27 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 2719863-7 |
| ISSN | 2051-1426 ; 2051-1426 |
| ISSN (online) | 2051-1426 |
| ISSN | 2051-1426 |
| DOI | 10.1136/jitc-2023-008608 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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