Department of Minimally Invasive Interventional Radiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
Central Laboratory, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.
Nat Commun. 2022 Oct 19;13(1):6203. doi: 10.1038/s41467-022-33968-5.
The complex immunosuppressive tumour microenvironment (TME) and lack of tumour-specific targets hinder the application of chimeric antigen receptor (CAR) T cells in the treatment of solid tumours. Combining local treatment with CAR T cell immunotherapy may regulate the TME and enhance the killing potency of CAR T cells in solid tumours. Here, we show that AXL, which is highly expressed in non-small cell lung cancer (NSCLC) but not in normal tissues, might be a target for CAR T cell therapy. AXL-CAR T cells alone cause moderate tumour regression in subcutaneous and pulmonary metastatic lung cancer cell-derived xenograft models. Combination of microwave ablation (MWA) and AXL-CAR T cells have superior antitumour efficacy. MWA enhances the activation, infiltration, persistence and tumour suppressive properties of AXL-CAR T cells in AXL-positive NSCLC patient-derived xenograft tumours via TME remodelling. The combination therapy increases the mitochondrial oxidative metabolism of tumour-infiltrating CAR T cells. Combination treatment induces significant tumour suppression without observed toxicities in humanized immunocompetent mice. The synergistic therapeutic effect of MWA and AXL-CAR T cells may be valuable for NSCLC treatment.
复杂的免疫抑制性肿瘤微环境(TME)和缺乏肿瘤特异性靶点,阻碍了嵌合抗原受体(CAR)T 细胞在实体瘤治疗中的应用。将局部治疗与 CAR T 细胞免疫疗法相结合,可能调节 TME 并增强 CAR T 细胞在实体瘤中的杀伤效力。在这里,我们表明,在非小细胞肺癌(NSCLC)中高度表达但在正常组织中不表达的 AXL 可能是 CAR T 细胞治疗的靶点。AXL-CAR T 细胞单独在皮下和肺转移肺癌细胞衍生的异种移植模型中引起中度肿瘤消退。微波消融(MWA)和 AXL-CAR T 细胞联合具有更好的抗肿瘤疗效。MWA 通过重塑 TME,增强了 AXL 阳性 NSCLC 患者来源异种移植肿瘤中 AXL-CAR T 细胞的激活、浸润、持续存在和肿瘤抑制特性。联合治疗增加了肿瘤浸润 CAR T 细胞的线粒体氧化代谢。在人源化免疫功能正常的小鼠中,联合治疗没有观察到毒性,却显著抑制了肿瘤。MWA 和 AXL-CAR T 细胞的协同治疗效果可能对 NSCLC 的治疗具有重要价值。
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