Cargando…
CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality
Tumor-derived extracellular vesicles (EVs) are active contributors in metastasis and immunosuppression in tumor microenvironment. At least some of the EVs carry tumor surface molecules such as tumor-associated antigens (TAAs) and/or checkpoint inhibitors, and potentially could interact with T cells...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832131/ https://www.ncbi.nlm.nih.gov/pubmed/36627334 http://dx.doi.org/10.1038/s41598-023-27604-5 |
_version_ | 1784867997775560704 |
---|---|
author | Ukrainskaya, V. M. Musatova, O. E. Volkov, D. V. Osipova, D. S. Pershin, D. S. Moysenovich, A. M. Evtushenko, E. G. Kulakovskaya, E. A. Maksimov, E. G. Zhang, H. Rubtsov, Y. P. Maschan, M. A. Stepanov, A. V. Gabibov, A. G. |
author_facet | Ukrainskaya, V. M. Musatova, O. E. Volkov, D. V. Osipova, D. S. Pershin, D. S. Moysenovich, A. M. Evtushenko, E. G. Kulakovskaya, E. A. Maksimov, E. G. Zhang, H. Rubtsov, Y. P. Maschan, M. A. Stepanov, A. V. Gabibov, A. G. |
author_sort | Ukrainskaya, V. M. |
collection | PubMed |
description | Tumor-derived extracellular vesicles (EVs) are active contributors in metastasis and immunosuppression in tumor microenvironment. At least some of the EVs carry tumor surface molecules such as tumor-associated antigens (TAAs) and/or checkpoint inhibitors, and potentially could interact with T cells or CAR T cells. Upon contact with T cells, EVs could alter their phenotype and functions by triggering signaling through TCR or CAR reprogramming them to escape immune response. We hypothesize that EVs that possess TAA on the surface will probably interact with CAR T cells which can recognize and bind corresponding TAA. This interaction between EVs and CAR T cells may change the outcome of CAR T-based cancer immunotherapy since it should affect CAR T cells. Also, EVs could serve as adjuvants and antigenic components of antitumor vaccines. Herein, we isolated EVs from B cell precursor leukemia cell line (pre-B ALL) Nalm-6 and demonstrated that recognition and binding of CD19(+)EVs with CD19-CAR T cells strongly depends on the presence of CD19 antigen. CD19(+)EVs induce secretion of pro-inflammatory cytokines (IL-2 and IFN-y) and upregulated transcription of activation-related genes (IFNG, IFNGR1, FASLG, IL2) in CD19-CAR T cells. Tumor necrosis factor receptor superfamily (TNFRSF4 and TNFRSF9) and T-cell exhaustion markers (CTLA4, LAG3, TIM3 and PDCD1LG2) were also upregulated in CD19-CAR T cells after incubation with CD19(+)EVs. Long-term cultivation of CD19(+) or PD-L1(+)EVs with CD19-CAR T cells led to increased terminal differentiation and functional exhaustion according to elevated expression of PD-1, TIGIT, CD57. In summary, our results suggest that chronic exposure of CD19-CAR T cells to CD19(+)EVs mediates activation and systemic exhaustion in antigen-specific manner, and this negative effect is accompanied by the impaired cytotoxic activity in vitro. |
format | Online Article Text |
id | pubmed-9832131 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98321312023-01-12 CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality Ukrainskaya, V. M. Musatova, O. E. Volkov, D. V. Osipova, D. S. Pershin, D. S. Moysenovich, A. M. Evtushenko, E. G. Kulakovskaya, E. A. Maksimov, E. G. Zhang, H. Rubtsov, Y. P. Maschan, M. A. Stepanov, A. V. Gabibov, A. G. Sci Rep Article Tumor-derived extracellular vesicles (EVs) are active contributors in metastasis and immunosuppression in tumor microenvironment. At least some of the EVs carry tumor surface molecules such as tumor-associated antigens (TAAs) and/or checkpoint inhibitors, and potentially could interact with T cells or CAR T cells. Upon contact with T cells, EVs could alter their phenotype and functions by triggering signaling through TCR or CAR reprogramming them to escape immune response. We hypothesize that EVs that possess TAA on the surface will probably interact with CAR T cells which can recognize and bind corresponding TAA. This interaction between EVs and CAR T cells may change the outcome of CAR T-based cancer immunotherapy since it should affect CAR T cells. Also, EVs could serve as adjuvants and antigenic components of antitumor vaccines. Herein, we isolated EVs from B cell precursor leukemia cell line (pre-B ALL) Nalm-6 and demonstrated that recognition and binding of CD19(+)EVs with CD19-CAR T cells strongly depends on the presence of CD19 antigen. CD19(+)EVs induce secretion of pro-inflammatory cytokines (IL-2 and IFN-y) and upregulated transcription of activation-related genes (IFNG, IFNGR1, FASLG, IL2) in CD19-CAR T cells. Tumor necrosis factor receptor superfamily (TNFRSF4 and TNFRSF9) and T-cell exhaustion markers (CTLA4, LAG3, TIM3 and PDCD1LG2) were also upregulated in CD19-CAR T cells after incubation with CD19(+)EVs. Long-term cultivation of CD19(+) or PD-L1(+)EVs with CD19-CAR T cells led to increased terminal differentiation and functional exhaustion according to elevated expression of PD-1, TIGIT, CD57. In summary, our results suggest that chronic exposure of CD19-CAR T cells to CD19(+)EVs mediates activation and systemic exhaustion in antigen-specific manner, and this negative effect is accompanied by the impaired cytotoxic activity in vitro. Nature Publishing Group UK 2023-01-10 /pmc/articles/PMC9832131/ /pubmed/36627334 http://dx.doi.org/10.1038/s41598-023-27604-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ukrainskaya, V. M. Musatova, O. E. Volkov, D. V. Osipova, D. S. Pershin, D. S. Moysenovich, A. M. Evtushenko, E. G. Kulakovskaya, E. A. Maksimov, E. G. Zhang, H. Rubtsov, Y. P. Maschan, M. A. Stepanov, A. V. Gabibov, A. G. CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality |
title | CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality |
title_full | CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality |
title_fullStr | CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality |
title_full_unstemmed | CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality |
title_short | CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality |
title_sort | car-tropic extracellular vesicles carry tumor-associated antigens and modulate car t cell functionality |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832131/ https://www.ncbi.nlm.nih.gov/pubmed/36627334 http://dx.doi.org/10.1038/s41598-023-27604-5 |
work_keys_str_mv | AT ukrainskayavm cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT musatovaoe cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT volkovdv cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT osipovads cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT pershinds cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT moysenovicham cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT evtushenkoeg cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT kulakovskayaea cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT maksimoveg cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT zhangh cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT rubtsovyp cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT maschanma cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT stepanovav cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality AT gabibovag cartropicextracellularvesiclescarrytumorassociatedantigensandmodulatecartcellfunctionality |