肿瘤细胞治疗研究
英文原题：Glioblastoma stem cells as carriers of tumour memory: a strategy for personalised immunotherapy using tumour-infiltrating lymphocytes.
Glioblastoma stem cells as carriers of tumour memory: a strategy for personalised immunotherapy using tumour-infiltrating lymphocytes.
胶质母细胞瘤（GB）仍然是最具侵袭性的脑肿瘤之一，中位生存期为15个月，这主要归因于对现有抗癌疗法（包括前沿免疫疗法）的耐药性。
胶质母细胞瘤（GB）仍然是最具侵袭性的脑肿瘤之一，中位生存期为15个月，这在很大程度上是由于对现有抗癌疗法（包括前沿免疫治疗）的耐药性。越来越多的证据表明，癌症干细胞（CSCs）参与了针对现有治疗模式耐药性的升级，这归因于其表型可塑性、耐药泵表达升高以及免疫调节行为。这些致癌后果由若干表观遗传重编程事件调控，而这些事件在维持与CSC介导的治疗耐药及后续致癌进展相关的适应性特征方面至关重要。在本综述中，我们将此类表观遗传后果视为“肿瘤记忆”，并试图通过针对CSCs——即“肿瘤记忆的携带者”——在GB中通过免疫干预来揭示治疗脆弱性。有趣的是，基于免疫的抗癌疗法正走到癌症研究的前沿，其中T淋巴细胞被免疫增强以攻击肿瘤细胞。然而，现实中，此类程序仍承受若干限制。在此背景下，以骨髓来源细胞为主导的GB微环境将浸润的免疫细胞重编程为抑制性表型，形成“冷”免疫景观。功能活跃淋巴细胞得以保留的唯一区域是肿瘤的侵袭边缘，在那里它们沿TPE → TEX轴发生耗竭，但仍保留增殖潜能。在此基础上，我们引入“侵袭边缘淋巴细胞”（IMLs）的概念，其中干细胞样记忆T细胞（TSCM）对于长期免疫保护不可或缺，因为它们具有独特的增殖潜能和长期持续存在的能力。值得注意的是，此类TSCM与CSC具有惊人的相似性，因为这两种细胞类型均采用WNT/β-catenin信号通路、层级组织和DNA修复系统等进化上保守的机制。因此，理解CSC-TSCM双向交互作用可为开发个性化TIL为基础的治疗提供启发式基础，该治疗旨在抑制层级组织的CSC群体并克服CSC引导的免疫治疗耐药。在本文综述中，我们在GB CSC与TSCM之间进行概念类比，提出三阶段治疗策略：浸润边缘的精准细胞减灭、使用癌症疫苗和药理剂“加热”微环境，以及过继转移源自IML池的TIL以确保持久疾病控制。
Glioblastoma (GB) remains one of the most aggressive brain tumours, with a median survival of 15 months, largely due to resistance towards available anti-cancer therapies, including cutting-edge immunotherapy. Growing evidence indicates involvement of cancer stem cells (CSCs) in escalating resistance against existing treatment modalities due to their phenotypic plasticity, elevated expression of drug-resistance pumps, and immunomodulatory behaviour. Such oncogenic consequences are regulated by several epigenetic reprogramming events that are pivotal in retaining adaptive traits associated with CSC-mediated therapy resistance and subsequent oncogenic progression. In this review, we consider such epigenetic consequences as "tumour memory" and try to shed light on the therapeutic vulnerabilities by targeting CSCs - the "carriers of tumour memory" - via immune interventions in GB. Interestingly, immune-based anti-cancer therapies are coming to the forefront of cancer research, where T lymphocytes are immunologically boosted to attack tumour cells. However, in reality, several constraints burden such procedures. Contextually, the GB microenvironment, dominated by bone marrow-derived cells, reprograms infiltrating immune cells into suppressor phenotypes, creating a "cold" immune landscape. The only zone where functionally active lymphocytes are preserved is the invasive margin of the tumour, where they undergo exhaustion along the TPE → TEX axis but retain proliferative potential. On this basis, we introduce the concept of "invasive margin lymphocytes" (IMLs), of which stem-like memory T cells (TSCM) are indispensable for long-term immunological protection, as they have unique proliferative potential and ability for long-term persistence. Incidentally, such TSCMs have striking similarities with CSCs, as both cell types employ evolutionarily conserved mechanisms of the WNT/β-catenin signalling pathway, hierarchical organisation, and DNA repair systems. Therefore, understanding CSC-TSCM bidirectional cross-talk could provide a heuristic basis for developing personalised TIL-based therapy aimed at suppressing the hierarchically organised CSC population and overcoming CSC-guided immunotherapy resistance. Drawing conceptual parallels between GB CSCs and TSCM, here in this review, we propose a three-stage therapeutic strategy: precision cytoreduction of the invasive margin, "warming up" the microenvironment using cancer vaccines and pharmacological agents, as well as adoptive transfer of TILs derived from the IML pool to ensure durable disease control.
MEMBER ACCOUNT
登录成功会直接打开下一页。
