Zhang Xiaoshuai, Guo Haiyan, Chen Jie, Xu Chenxiao, Wang Lei, Ke Yong, Gao Yang, Zhang Baohong, Zhu Jianwei
Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Cancer Lett. 2023 Sep 28;572:216355. doi: 10.1016/j.canlet.2023.216355. Epub 2023 Aug 18.
Chimeric antigen receptor (CAR)-T cell immunotherapy is highly effective against hematological neoplasms. However, owing to tumor variability, low antigen specificity, and impermanent viability of CAR-T cells, their use in the treatment of solid tumors is limited. Here, a novel CAR-T cell targeting B7-H3 and incorporating a 4-1BB costimulatory molecule with STAT3-and STAT5-related activation motifs was constructed using lentivirus transduction. B7-H3, a tumor-associated antigen, and its scFv antibody endowed CAR-T cells with tumor-specific targeting capabilities. Moreover, the integration of the trIL2RB and YRHQ motifs stimulated STAT5 and STAT3 in an antigen-dependent manner, inducing a remarkable increase in the proliferation and survival of CAR-T cells via the activation of the JAK-STAT signaling pathway. Besides, the proportion of less-differentiated T cells increased among BB-trIL2RB-z(YRHQ) CAR-T cells. Moreover, BB-trIL2RB-z(YRHQ) effectively inhibited ovarian cancer (OC) and triple-negative breast cancer (TNBC) in vivo at low doses, without high serum levels of inflammatory cytokines and organ toxicity. Therefore, our study proposes a combination of elements for the construction of superior pluripotent CAR-T cells to provide an effective strategy for the treatment of intractable solid tumors.
嵌合抗原受体（CAR）-T细胞免疫疗法对血液系统肿瘤具有高度有效性。然而，由于肿瘤的变异性、低抗原特异性以及CAR-T细胞的短暂生存能力，它们在实体瘤治疗中的应用受到限制。在此，利用慢病毒转导构建了一种新型的靶向B7-H3并整合了带有STAT3和STAT5相关激活基序的4-1BB共刺激分子的CAR-T细胞。肿瘤相关抗原B7-H3及其单链抗体片段（scFv）赋予了CAR-T细胞肿瘤特异性靶向能力。此外，trIL2RB和YRHQ基序的整合以抗原依赖的方式刺激STAT5和STAT3，通过激活JAK-STAT信号通路诱导CAR-T细胞的增殖和存活显著增加。此外，在BB-trIL2RB-z（YRHQ）CAR-T细胞中，低分化T细胞的比例增加。而且，BB-trIL2RB-z（YRHQ）在低剂量下能有效抑制体内卵巢癌（OC）和三阴性乳腺癌（TNBC），且不会导致血清中炎症细胞因子水平升高和器官毒性。因此，我们的研究提出了构建卓越多能CAR-T细胞的多种要素组合，为治疗难治性实体瘤提供了一种有效策略。
