Sanghee Shin a,1, Inseong Jung a,1, Dokyung Jung c, Christine Seulki Kim a, Sung-Min Kang c, Suyeon Ryu c, Sung-Jin Choi a, Soojeong Noh a, Jongwon Jeong a, Beom Yong Lee a, Jun-Kook Park a, Jiwon Shin a, Hanchae Cho c, Jong-Ik Heo a, Youngtae Jeong a, Sun Ha Choi d,e, Shin Yup Lee d,e, Moon-Chang Baek c,*, Kyungmoo Yea a,b,*
a Department of New Biology, DGIST, Daegu, 42988, Republic of Korea b New Biology Research Center, DGIST, Daegu, 43024, Republic of Korea c Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea d Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea e Lung Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, 41404, Republic of Korea
* Corresponding author.
1 S. Shin and I. Jung contributed equally to this work.
Extracellular vesicles (EVs) mediate cell-cell crosstalk by carrying bioactive molecules derived from cells. Recently, immune cell-derived EVs have been reported to regulate key biological functions such as tumor progression. CD4+ T cells orchestrate overall immunity; however, the biological role of their EVs is unclear. This study reveals that EVs derived from CD4+ T cells increase the antitumor response of CD8+ T cells by enhancing their proliferation and activity without affecting regulatory T cells (Tregs). Moreover, EVs derived from interleukin-2 (IL2)-stimulated CD4+ T cells induce a more enhanced antitumor response of CD8+ T cells compared with that of IL2-unstimulated CD4+ T cell-derived EVs. Mechanistically, miR-25-3p, miR-155-5p, miR-215-5p, and miR-375 within CD4+ T cell-derived EVs are responsible for the induction of CD8+ T cell-mediated antitumor responses. In a melanoma mouse model, the EVs potently suppress tumor growth through CD8+ T cell activation. This study demonstrates that the EVs, in addition to IL2, are important mediators between CD4+ and CD8+ T cells. Furthermore, unlike IL2, clinically used as an antitumor agent, CD4+ T cell-derived EVs stimulate CD8+ T cells without activating Tregs. Therefore, CD4+ T cell-derived EVs may provide a novel direction for cancer immunotherapy by inducing a CD8+ T cell-mediated antitumor response.