CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality.

Autor: Ukrainskaya VM; M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russian Federation, 117997.; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, 117997., Musatova OE; M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russian Federation, 117997., Volkov DV; M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russian Federation, 117997., Osipova DS; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, 117997., Pershin DS; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, 117997., Moysenovich AM; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russian Federation, 119991., Evtushenko EG; Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russian Federation, 119991., Kulakovskaya EA; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, 117997., Maksimov EG; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russian Federation, 119991., Zhang H; State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin, 300071, China., Rubtsov YP; M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russian Federation, 117997.; Blokhin National Medical Research Center of Oncology, Ministry of Health, Moscow, Russian Federation., Maschan MA; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, 117997., Stepanov AV; Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road MB-10, La Jolla, CA, 92037, USA. stepanov@scripps.edu., Gabibov AG; M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russian Federation, 117997. gabibov@mx.ibch.ru.; Higher School of Economics, Moscow, Russian Federation, 101000. gabibov@mx.ibch.ru.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Jan 10; Vol. 13 (1), pp. 463. Date of Electronic Publication: 2023 Jan 10.
DOI: 10.1038/s41598-023-27604-5
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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