Cao, Liu, and Xiao et al. examined the effect of combining microwave ablation (MWA) with sCAR T cells secreting CV1 (a short lived, affinity-enhanced SIRPα that blocks CD47 signaling) on the abscopal effect in antigen-heterogeneous tumor models that respond poorly to CAR T cell therapy alone. As in humans, MWA alone elicited a weak abscopal response. However, MWA plus sCAR-T secreting CV1 not only potentiated local antitumor effects, but stimulated chemokine production by ablated tumors, which recruited and activated macrophages, promoted M1 polarization, and enhanced phagocytosis at distant non-ablated tumor sites, without added systemic toxicity.
Contributed by Katherine Turner
ABSTRACT: Microwave ablation (MWA) triggers a weak systemic immune response that leads to the abscopal regression of distant metastases while killing local tumors, known as the abscopal effect. Combining MWA with chimeric antigen receptor (CAR)-T cells demonstrates promise in enhancing the abscopal effect in antigen-homogeneous tumors. However, the loss of the antigen recognized by CAR or intrinsic antigenic heterogeneity in solid tumors poses a major obstacle. SIRP_ variant (CV1)-secreting CAR-T (sCAR-T) cells elicit an abscopal effect on distant tumors with antigen heterogeneity in mice receiving local MWA. Mechanistically, sCAR-T cells can locally eliminate antigen-positive tumors and secrete CV1, whereas the secreted CV1 can activate macrophages that migrate to non-ablated tumor sites in response to post-MWA chemokines, eliciting a macrophage-dependent abscopal effect that enables phagocytosis of antigen-heterogeneous cancer cells. This macrophage-dependent abscopal effect instigated by MWA and sCAR-T cells offers a clinically translatable strategy in metastatic solid tumors with antigen heterogeneity.
Author Info: (1) Department of Minimally Invasive Interventional Radiology, Department of Radiology, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou,
Author Info: (1) Department of Minimally Invasive Interventional Radiology, Department of Radiology, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China; Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA. (2) Department of Minimally Invasive Interventional Radiology, Department of Radiology, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China. (3) Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China. (4) MoE Frontiers Science Center for Precision Oncology, Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China. (5) Department of Library, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. (6) Department of Minimally Invasive Interventional Radiology, Department of Radiology, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China. (7) Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510080, China. (8) Department of Minimally Invasive Interventional Radiology, Department of Radiology, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China. (9) Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore. (10) Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. (11) The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel. (12) MoE Frontiers Science Center for Precision Oncology, Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China. Electronic address: qizhao@um.edu.mo. (13) Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: shen17@iu.edu. (14) Department of Minimally Invasive Interventional Radiology, Department of Radiology, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China. Electronic address: zhksh010@163.com.
