Sci Rep, 2023, 13(1):463

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 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 CD19EVs with CD19-CAR T cells strongly depends on the presence of CD19 antigen. CD19EVs 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 CD19EVs. Long-term cultivation of CD19 or PD-L1EVs 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 CD19EVs mediates activation and systemic exhaustion in antigen-specific manner, and this negative effect is accompanied by the impaired cytotoxic activity in vitro.

Ukrainskaya VM, Musatova OE, Volkov DV, Osipova DS, Pershin DS, Moysenovich AM, Evtushenko EG, Kulakovskaya EA, Maksimov EG, Zhang H, Rubtsov YP, Maschan MA, Stepanov AV, Gabibov AG

IBCH: 10470
Ссылка на статью в журнале: https://www.nature.com/articles/s41598-023-27604-5
Кол-во цитирований на 09.2024: 10
Данные статьи проверены модераторами 2023-01-13

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