Remodelling of tumour microenvironment by microwave ablation potentiates immunotherapy of AXL-specific CAR T cells against non-small cell lung cancer

Bihui Cao, Manting Liu, Lu Wang, Kangshun Zhu, Mingyue Cai, Xiaopei Chen, Yunfei Feng, Shuo Yang, Shengyu Fu, Cheng Zhi, Xiaodie Ye, Jian Zhang, Zhiru Zhang, Xin Yang, Ming Zhao, Qingde Wu, Linfeng Xu, Lili Yang, Hui Lian, Qi Zhao () and Zhenfeng Zhang ()
Additional contact information
Bihui Cao: the Second Affiliated Hospital of Guangzhou Medical University
Manting Liu: the Second Affiliated Hospital of Guangzhou Medical University
Lu Wang: the Second Affiliated Hospital of Guangzhou Medical University
Kangshun Zhu: the Second Affiliated Hospital of Guangzhou Medical University
Mingyue Cai: the Second Affiliated Hospital of Guangzhou Medical University
Xiaopei Chen: the Second Affiliated Hospital of Guangzhou Medical University
Yunfei Feng: the Second Affiliated Hospital of Guangzhou Medical University
Shuo Yang: University of Macau
Shengyu Fu: University of Macau
Cheng Zhi: the Second Affiliated Hospital of Guangzhou Medical University
Xiaodie Ye: the Second Affiliated Hospital of Guangzhou Medical University
Jian Zhang: the Second Affiliated Hospital of Guangzhou Medical University
Zhiru Zhang: the Second Affiliated Hospital of Guangzhou Medical University
Xin Yang: the Second Affiliated Hospital of Guangzhou Medical University
Ming Zhao: Cancer Center, Sun Yat-sen University
Qingde Wu: Shunde Chinese Medicine Hospital, the Affiliated Hospital of Traditional Chinese Medicine University of Guangzhou
Linfeng Xu: Sun Yat-sen University
Lili Yang: Sun Yat-sen University
Hui Lian: the Second Affiliated Hospital of Guangzhou Medical University
Qi Zhao: University of Macau
Zhenfeng Zhang: the Second Affiliated Hospital of Guangzhou Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33968-5

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