Surface-engineered extracellular vesicles to modulate antigen-specific T cell expansion for cancer immunotherapy

Lyu, X.; Yamano, T.; Imai, S.; Le, T. V.; Bolidong, D.; Ueda, M.; Warashina, S.; Mukai, H.; Hayashi, S.; Matoba, K.; Nishino, T.; Hanayama, R.

doi:10.1101/2023.09.25.559260

bioRxiv · 10.1101/2023.09.25.559260

Surface-engineered extracellular vesicles to modulate antigen-specific T cell expansion for cancer immunotherapy

Lyu, X.·Yamano, T.·Imai, S.·Le, T. V.·Bolidong, D.·Ueda, M.·Warashina, S.·Mukai, H.·Hayashi, S.·Matoba, K.·Nishino, T.·Hanayama, R.

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Abstract

Extracellular vesicles (EVs), including exosomes, are emerging as novel mediators of cell-cell communications, involved in various processes such as immune activation and immunosuppression. Despite the recent development of several EVs-based cancer immunotherapies, their clinical efficacy remained limited. Here, using fusion with tetraspanin as one of the EV engineering techniques, we created antigen-presenting extracellular vesicles (AP-EVs) to reproduce the functional characteristics of professional antigen-presenting cells (APCs). AP-EVs were also equipped with surface-bound IL-2, a feature not inherent to APCs, which facilitated selective delivery of IL-2 to antigen-specific CD8+ T cells. AP-EVs were engineered to express a peptide-major histocompatibility class I (pMHCI) complex, a costimulatory CD80 molecule, and IL-2, allowing the simultaneous presentation of multiple immune modulators to antigen-specific CD8+ T cells. This promoted the clonal expansion and differentiation of antigen-specific cytotoxic T lymphocytes, leading to potent anticancer immune responses. Combination therapy with AP-EVs and anti-PD-1 demonstrated enhanced anticancer immunity against established tumors compared with anti-PD-1 monotherapy. Our engineered EVs represent a novel effective strategy for cancer immunotherapy.

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Lyu, X., Yamano, T., Imai, S., Le, T. V., Bolidong, D., Ueda, M., Warashina, S., Mukai, H., Hayashi, S., Matoba, K., Nishino, T., Hanayama, R.. 2023-09-25. Surface-engineered extracellular vesicles to modulate antigen-specific T cell expansion for cancer immunotherapy. https://doi.org/10.1101/2023.09.25.559260

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