Kim Sojeong, Kwak Jeong-Eun, Koh June-Young, Lee Ji Eun, Kook Hye Won, Kim Minchae, Chung Haerim, Kim Yu Ri, Kim Soo Jeong, Kim Jin Seok, Cheong June-Won, Lee Min Goo, Lee Hoyoung, Park Su-Hyung, Shin Eui-Cheol, Shin Saeam, Yoon Sun Och, Choi Il-Kyu, Lee Jeong Seok, Cho Hyunsoo
Blood Cancer Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Blood. 2025 Jul 24;146(4):456-470. doi: 10.1182/blood.2024025875.
Emerging evidence indicates that CD4+ T cells contribute to antitumor immunity beyond their traditional roles as helpers or regulators. However, the specific subset of CD4+ T cells mediating beneficial outcomes in patients with multiple myeloma remains unclear. Here, we performed single-cell RNA sequencing and T-cell receptor sequencing on CD4+ T cells sorted from the bone marrow of patients across the stages of myeloma progression. We identified several distinct states of CD4+ cytotoxic T lymphocytes (CTLs) that were significantly increased and clonally expanded in patients with myeloma. CD4+ CTLs displayed transcriptional and phenotypic characteristics indicative of cytotoxicity, demonstrating their ability to directly kill myeloma cells. This cytotoxicity, however, was abrogated by NKG2D blockade. Notably, the abundance of NKG2D+CD4+ CTLs correlated with improved survival in patients with myeloma. Our findings suggest that harnessing CD4+ CTLs could lead to novel strategies for enhancing immunotherapy outcomes in multiple myeloma.
新出现的证据表明，CD4+ T细胞在抗肿瘤免疫中的作用超出了其作为辅助细胞或调节细胞的传统角色。然而，介导多发性骨髓瘤患者产生有益结果的CD4+ T细胞的具体亚群仍不清楚。在这里，我们对从骨髓瘤进展各阶段患者骨髓中分离出的CD4+ T细胞进行了单细胞RNA测序和T细胞受体测序。我们鉴定出几种不同状态的CD4+ 细胞毒性T淋巴细胞（CTL），它们在骨髓瘤患者中显著增加且克隆性扩增。CD4+ CTL表现出指示细胞毒性的转录和表型特征，证明它们能够直接杀死骨髓瘤细胞。然而，这种细胞毒性被NKG2D阻断所消除。值得注意的是，NKG2D+CD4+ CTL的丰度与骨髓瘤患者的生存改善相关。我们的研究结果表明，利用CD4+ CTL可能会带来增强多发性骨髓瘤免疫治疗效果的新策略。
