홍창완 (부산대학교 의과대학)

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부산대학교 의과대학

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Mol. Ther., August 21, 2024 | https://doi.org/10.1016/j.ymthe.2024.08.019 Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells

Yuna Jo ^1,2, Ju A Shim ^1,2, Jin Woo Jeong ^1,2,3, Hyori Kim ^1,2,3, So Min Lee ^1,2,3, Juhee Jeong ⁴, Segi Kim ⁵, Sun-Kyoung Im ⁶, Donghoon Choi ⁶, Byung Ha Lee⁷, Yun Hak Kim ^1,2, Chi Dae Kim ⁸, Chan Hyuk Kim ⁵, Changwan Hong ^1,2,3*

¹Department of Anatomy, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea

²Department of Convergence Medical Science, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea

³PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea

⁴Department of Anatomy and Cell Biology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.

⁵Department of Biological Sciences, Korea Advanced Institute of Science and Technology,Daejeon,34141, Republic of Korea

⁶NeoImmunetech, Co., Ltd., Pohang,37666, Republic of Korea

⁷NeoImmunetech, Inc., Rockville,20850, MD, USA

⁸Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea

^*Corresponding author: correspondence to Changwan Hong

Abstract

Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates the CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor-erythroid 2-related-2 (Nrf2) is ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8⁺ T and chimeric antigen receptor (CAR)-T cells under ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2^-/- mice was significantly controlled and was reversed by T cell depletion and further confirmed that Nrf2 deficiency in T cells promotes anti-tumor responses using adoptive transfer model of antigen-specific CD8⁺ T cells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in TME. Furthermore, Nrf2 knockdown in human CAR-T cells enhanced the survival and function of intratumoral CAR-T cells in solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor T cell responses, indicating that Nrf2 may be a potential target for T cell immunotherapy strategies against solid tumors.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-22)
연구진국내 연구진
분야 의약학 > 면역의학

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