Kim Seong A, Kim Seohyun, Hong Yeonsun, Choi Yoonjeong, Lee Yeji, Kwon Minsu, Park Seung-Yoon, Jeong Cherlhyun, Nam Gi-Hoon, Han Rafael T, Kim In-San
KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; Department of Research and Development, ShiftBio, Seoul 02751, Republic of Korea.
Transl Oncol. 2025 Jan;51:102209. doi: 10.1016/j.tranon.2024.102209. Epub 2024 Nov 27.
Immune checkpoint inhibition shows promise for cancer treatment, but only a minority of patients respond. Combination strategies have been explored to overcome this resistance. Combining immunogenic clearance using immunogenic cell death inducers with a rho kinase inhibitor enhances phagocytosis of immunogenically dying cancer cells by antigen-presenting cells, stimulating tumor-specific immune responses by activating CD8T cells via dendritic cell-mediated priming. This approach increases the responsiveness of immune checkpoint blockade (ICB)-resistant cancer to ICB. However, the precise mechanisms remain unclear. This study elucidates cellular mechanisms of immunogenic clearance enhancing ICB response. Using single-cell RNA sequencing, we observed an increase in effector memory-like CD8T cells within the tumor microenvironment with combined treatment. We propose this cell cluster may originate from proliferating CD8T cells elevated by immunogenic clearance. Notably, abundant effector memory-like CD8T cells in ICB-responsive patients suggest their antitumor effect. Thus, increasing this cell population through enhanced T cell priming may improve the response of ICB-resistant tumors.
免疫检查点抑制在癌症治疗中显示出前景,但只有少数患者有反应。人们已经探索了联合策略来克服这种耐药性。将使用免疫原性细胞死亡诱导剂的免疫原性清除与一种 Rho 激酶抑制剂相结合,可增强抗原呈递细胞对免疫原性死亡癌细胞的吞噬作用,通过树突状细胞介导的启动激活 CD8 T 细胞来刺激肿瘤特异性免疫反应。这种方法增加了对免疫检查点阻断(ICB)耐药的癌症对 ICB 的反应性。然而,确切机制仍不清楚。本研究阐明了增强 ICB 反应的免疫原性清除的细胞机制。通过单细胞 RNA 测序,我们观察到联合治疗后肿瘤微环境中效应记忆样 CD8 T 细胞增加。我们提出这个细胞簇可能起源于因免疫原性清除而增加的增殖性 CD8 T 细胞。值得注意的是,ICB 反应性患者中丰富的效应记忆样 CD8 T 细胞表明了它们的抗肿瘤作用。因此,通过增强 T 细胞启动来增加这个细胞群体可能会改善对 ICB 耐药肿瘤的反应。
J Immunother Cancer. 2021-8
Nat Rev Cancer. 2023-4
Trends Immunol. 2022-7