Oncogenesis ( IF 6.2 ) Pub Date : 2021-09-21 , DOI: 10.1038/s41389-021-00353-8 Yaoxin Gao 1 , Haizhen Lin 1 , Dandan Guo 1 , Sijia Cheng 1 , Ying Zhou 1 , Li Zhang 1 , Jie Yao 1 , Muhammad Asad Farooq 1 , Iqra Ajmal 1 , Yixin Duan 1 , Cong He 1 , Lei Tao 1 , Shijia Wu 1 , Mingyao Liu 1 , Wenzheng Jiang 1
Pancreatic carcinoma (PC) is one of the most common malignancies. Chimeric antigen receptor (CAR)-modified T cells has achieved remarkable efficacy in the treatment of hematological malignancies. However, lack of tumor-specific targets and the existence of inhibitory factors limit the function of CAR T cells when treating solid tumors. 4.1R has been reported to suppress the anti-tumor activity of T cell responses. In this study, we investigated the anti-tumor activity of 4.1R deletion in natural killer group 2D (NKG2D)-CAR T cells against PC. The CAR T cells were obtained by transfecting T cells with lentiviral vector carrying NKG2D-CAR, NC-NKG2D-CAR, or KD2-NKG2D-CAR. In vitro, NKG2D-CAR T cells showed higher cytotoxicity than Mock T cells. However, compared to NKG2D-CAR T cells, furtherly higher cytotoxicity against PC cells in a dose-dependent manner was found in KD2-NKG2D-CAR T cells. In addition, the proliferation rate and cytotoxic activity of KD2-NKG2D-CAR T cells were significantly higher than those of NKG2D-CAR T cells. Besides, the inhibitory receptors PD-1 and TIM-3 were expressed in lower level on KD2-NKG2D-CAR T cells. In vivo, KD2-NKG2D-CAR T cells suppressed tumor growth more effectively in a xenograft model compared to NKG2D-CAR T cells. Mechanistically, 4.1R regulated CAR T cell function via activating ERK signaling pathway. Therefore, the study provides a new idea to enhance the anti-tumor efficiency of CAR T therapy.
中文翻译:
抑制 4.1R 通过激活 ERK 信号通路增强 NKG2D-CAR T 细胞对抗胰腺癌的效力
胰腺癌(PC)是最常见的恶性肿瘤之一。嵌合抗原受体 (CAR) 修饰的 T 细胞在治疗血液系统恶性肿瘤方面取得了显着疗效。然而,缺乏肿瘤特异性靶点和抑制因子的存在限制了 CAR T 细胞在治疗实体瘤时的功能。据报道,4.1R 可抑制 T 细胞反应的抗肿瘤活性。在这项研究中,我们研究了自然杀伤组 2D (NKG2D)-CAR T 细胞中 4.1R 缺失对 PC 的抗肿瘤活性。通过用携带NKG2D-CAR、NC-NKG2D-CAR或KD2-NKG2D-CAR的慢病毒载体转染T细胞获得CAR T细胞。在体外,NKG2D-CAR T 细胞显示出比模拟 T 细胞更高的细胞毒性。然而,与NKG2D-CAR T细胞相比,在 KD2-NKG2D-CAR T 细胞中还发现了以剂量依赖性方式对 PC 细胞的更高细胞毒性。此外,KD2-NKG2D-CAR T细胞的增殖率和细胞毒活性显着高于NKG2D-CAR T细胞。此外,抑制性受体PD-1和TIM-3在KD2-NKG2D-CAR T细胞上的表达水平较低。在体内,与 NKG2D-CAR T 细胞相比,KD2-NKG2D-CAR T 细胞在异种移植模型中更有效地抑制了肿瘤生长。从机制上讲,4.1R 通过激活 ERK 信号通路调节 CAR T 细胞功能。因此,该研究为提高CAR-T疗法的抗肿瘤效率提供了新思路。此外,抑制性受体PD-1和TIM-3在KD2-NKG2D-CAR T细胞上的表达水平较低。在体内,与 NKG2D-CAR T 细胞相比,KD2-NKG2D-CAR T 细胞在异种移植模型中更有效地抑制了肿瘤生长。从机制上讲,4.1R 通过激活 ERK 信号通路调节 CAR T 细胞功能。因此,该研究为提高CAR-T疗法的抗肿瘤效率提供了新思路。此外,抑制性受体PD-1和TIM-3在KD2-NKG2D-CAR T细胞上的表达水平较低。在体内,与 NKG2D-CAR T 细胞相比,KD2-NKG2D-CAR T 细胞在异种移植模型中更有效地抑制了肿瘤生长。从机制上讲,4.1R 通过激活 ERK 信号通路调节 CAR T 细胞功能。因此,该研究为提高CAR-T疗法的抗肿瘤效率提供了新思路。