PDF(Pubmed)
Abstract：
Chimeric antigen receptor (CAR)-T cell therapy represents one of the most innovative immunotherapy approaches. The encouraging results achieved by CAR-T cell therapy in hematological disorders paved the way for the employment of CAR engineered T cells in different types of solid tumors. This adoptive cell therapy represents a selective and efficacious approach to eradicate tumors through the recognition of tumor-associated antigens (TAAs). Binding of engineered CAR-T cells to TAAs provokes the release of several cytokines, granzyme, and perforin that ultimately lead to cancer cells elimination and patient\'s immune system boosting. Within the tumor mass a subpopulation of cancer cells, known as cancer stem cells (CSCs), plays a crucial role in drug resistance, tumor progression, and metastasis. CAR-T cell therapy has indeed been exploited to target CSCs specific antigens as an effective strategy for tumor heterogeneity disruption. Nevertheless, a barrier to the efficacy of CAR-T cell-based therapy is represented by the poor persistence of CAR-T cells into the hostile milieu of the CSCs niche, the development of resistance to single targeting antigen, changes in tumor and T cell metabolism, and the onset of severe adverse effects. CSCs resistance is corroborated by the presence of an immunosuppressive tumor microenvironment (TME), which includes stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and immune cells. The relationship between TME components and CSCs dampens the efficacy of CAR-T cell therapy. To overcome this challenge, the double strategy based on the use of CAR-T cell therapy in combination with chemotherapy could be crucial to evade immunosuppressive TME. Here, we summarize challenges and limitations of CAR-T cell therapy targeting CSCs, with particular emphasis on the role of TME and T cell metabolic demands.
摘要：
嵌合抗原受体(CAR)-T细胞疗法代表了最具创新性的免疫治疗方法之一。CAR-T细胞疗法在血液系统疾病中取得的令人鼓舞的结果为CAR工程化T细胞在不同类型的实体瘤中的应用铺平了道路。这种过继细胞疗法代表了通过识别肿瘤相关抗原(TAA)根除肿瘤的选择性和有效的方法。工程化CAR-T细胞与TAA的结合激发了几种细胞因子的释放，granzyme,和穿孔素，最终导致癌细胞消除和患者的免疫系统增强。在肿瘤块内有一个癌细胞亚群，被称为癌症干细胞（CSC），在耐药性中起着至关重要的作用，肿瘤进展，和转移。CAR-T细胞疗法确实已被用于靶向CSC特异性抗原作为肿瘤异质性破坏的有效策略。然而，CAR-T细胞疗法功效的障碍表现为CAR-T细胞在CSC生态位的敌对环境中的持久性差。对单一靶向抗原的抗性的发展，肿瘤和T细胞代谢的变化，以及严重不良反应的发生。CSC抗性由免疫抑制肿瘤微环境（TME）的存在证实，其中包括基质细胞，癌症相关成纤维细胞（CAFs），肿瘤相关巨噬细胞（TAMs），骨髓来源的抑制细胞（MDSCs），和免疫细胞。TME组分和CSC之间的关系抑制了CAR-T细胞疗法的功效。为了克服这一挑战，基于CAR-T细胞疗法联合化疗的双重策略可能对逃避免疫抑制性TME至关重要.这里,我们总结了针对CSC的CAR-T细胞疗法的挑战和局限性，特别强调TME和T细胞代谢需求的作用。
