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.
Proc Natl Acad Sci U S A. 2023 Sep 19;120(38):e2300366120. doi: 10.1073/pnas.2300366120. Epub 2023 Sep 11.
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.
基于免疫细胞的癌症疗法，如嵌合抗原受体 T (CAR-T)细胞免疫疗法，已证明对血液肿瘤具有令人印象深刻的疗效。然而，CAR-T 细胞对实体瘤的疗效仍然有限。在此，我们设计了肿瘤靶向分子-唾液酸酶缀合物，能够有效地、选择性地从各种癌细胞中去除不同的唾液酸糖。去唾液酸化增强了诱导多能干细胞衍生的嵌合抗原受体-巨噬细胞（CAR-iMac）的浸润和激活。此外，癌细胞去唾液酸化与 CAR-iMac 过继细胞疗法的联合对实体瘤产生了显著的治疗效果，并显著延长了荷瘤小鼠的生存时间；这些效果主要依赖于阻断巨噬细胞上唾液酸结合免疫球蛋白样凝集素（Siglec）-5 和 Siglec-10 组成的检查点，并且敲除糖免疫检查点受体可以构建具有更强抗癌活性的 CAR-iMac 细胞。这种将免疫逃逸状态（“冷肿瘤”）逆转回敏感识别状态（“热肿瘤”）的策略，对于增强细胞免疫疗法对实体瘤的疗效具有重要意义。因此，去唾液酸化联合 CAR-iMac 细胞免疫疗法是增强细胞免疫治疗效果和扩大实体瘤有效适应证的有前途的方法，为开发具有糖免疫检查点抑制作用的细胞免疫疗法治疗人类癌症提供了启示。
