Article ; Online: Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells.
2020 Volume 8, Issue 6, Page(s) 732–742
Abstract: Although clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve ... ...
| Abstract | Although clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve mechanisms of CAR T-cell failure. Because T-cell dysfunction is thought to contribute to CAR T-cell treatment failure, understanding what mechanisms drive T cells into this dysfunctional state may aid optimal design of efficacious CAR T cells. Dysfunctional CAR T cells have been characterized as having upregulated inhibitory receptors and decreased cytolytic capabilities. Previous studies have identified a role for sustained CAR CD3ζ signaling in CAR T-cell dysfunction. Here, we demonstrate a mechanism that drives dysfunction in CAR T cells through excessive costimulation. Fully activated CD19-targeted CAR T cells were rendered dysfunctional upon stimulation with both endogenous CD28 stimulation and CAR-mediated CD28 costimulation. Costimulation-driven dysfunction of CAR T cells was demonstrated in a syngeneic immunocompetent mouse model, in which CAR T cells were activated with signals 1 (CD3ζ), 2 (CD28), and 3 (IL12). Thus, we show that CAR T-cell dysfunction can be driven through excessive CD28 and 4-1BB costimulation. |
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| MeSH term(s) | Animals ; Antigens, CD19/immunology ; Antigens, CD19/metabolism ; Apoptosis ; CD28 Antigens/immunology ; CD28 Antigens/metabolism ; Cell Proliferation ; Cytokines ; Humans ; Immunotherapy, Adoptive/methods ; Interleukin-12/metabolism ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; Signal Transduction ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/pathology ; Thymoma/immunology ; Thymoma/metabolism ; Thymoma/pathology ; Thymus Neoplasms/immunology ; Thymus Neoplasms/metabolism ; Thymus Neoplasms/pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays |
| Chemical Substances | Antigens, CD19 ; CD28 Antigens ; Cytokines ; Interleukin-12 (187348-17-0) |
| Language | English |
| Publishing date | 2020-03-25 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2732489-8 |
| ISSN | 2326-6074 ; 2326-6066 |
| ISSN (online) | 2326-6074 |
| ISSN | 2326-6066 |
| DOI | 10.1158/2326-6066.CIR-19-0908 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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