Wu, Wang, and Huang et al. showed that surface sialic acids protect tumor cells through interactions with inhibitory receptors Siglec-5 and Siglec-10 on macrophages, including adoptively transferred iPSC-derived mesothelin-specific CAR macrophages (CAR-iMacs). In solid tumor models in immune-competent mice, CAR-iMac therapy could be enhanced by adding tumor-targeting molecule–sialidase conjugates or by knocking out Siglec-5 and -10, which enhanced the infiltration and activation of CAR-iMacs, increased phagocytosis, and mediated therapeutic antitumor effects and prolonged survival.
Contributed by Lauren Hitchings
ABSTRACT: Immune cell-based cancer therapies, such as chimeric antigen receptor T (CAR-T)-cell immunotherapy, have demonstrated impressive potency against hematological tumors. However, the efficacy of CAR-T cells against solid tumors remains limited. Herein, we designed tumor-targeting molecule-sialidase conjugates that potently and selectively stripped different sialoglycans from a variety of cancer cells. Desialylation enhanced induced pluripotent stem cell-derived chimeric antigen receptor-macrophage (CAR-iMac) infiltration and activation. Furthermore, the combination of cancer cell desialylation and CAR-iMac adoptive cellular therapy exerted a dramatic therapeutic effect on solid tumors and significantly prolonged the survival of tumor-bearing mice; these effects were mainly dependent on blockade of the checkpoint composed of sialic acid-binding immunoglobulin-like lectin (Siglec)-5 and Siglec-10 on the macrophages, and knockout of the glycoimmune checkpoint receptors could construct a CAR-iMac cell with stronger anticancer activity. This strategy that reverts the immune escape state ("cold tumor") to a sensitive recognition state ("hot tumor") has great significance for enhancing the effect of cellular immunotherapy on solid tumors. Therefore, desialylation combined with CAR-iMac cellular immunotherapy is a promising approach to enhance treatment with cellular immunotherapy and expand the valid indications among solid tumors, which provides inspiration for the development of cellular immunotherapies with glycoimmune checkpoint inhibition for the treatment of human cancer.
Author Info: (1) Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Med
Author Info: (1) Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China. Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China. (2) Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China. (3) Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China. (4) Ultrasonic Department, Renmin Hospital of Wuhan University, Wuhan 430060, China. (5) Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China. Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, China. (6) Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China. (7) Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China. (8) Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China. (9) Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China. Cancer Cancer, Zhejiang University, Hangzhou 310029, China.
