免疫治疗：治疗脑转移的新兴方法

脑转移（BrM）的诊断长期以来一直被视为毫无希望的死亡判决，几乎没有治疗选择可以缓解症状或延长生命。在少数可用的治疗选择中，脑部放疗（RT）和手术切除一直是治疗的基石。在过去几年中，免疫治疗（IT）作为一种重要力量，单独或与传统治疗联合应用，已经成为对抗脑转移瘤扩散和减小肿瘤负担的重要手段。本综述汇编了近期的研究报告，描述了IT在不同癌症脑转移瘤治疗中的潜在作用。本文还探讨了脑转移瘤肿瘤微环境对癌症扩散的调控作用，以及IT在减轻扩散中的作用。最后，本文还关注IT在脑转移瘤治疗中的未来发展和新的临床试验介绍。

最新的有关脑转移治疗的文献解读

图1. 脑转移的机制和免疫治疗进展时间表

1.  循环肿瘤细胞或转移细胞使原发性黑色素瘤、肺癌、乳腺癌、肾癌和结直肠癌通过血管侵犯进入血液或系统循环，到达大脑，并通过血脑屏障。在大脑中，这些转移细胞通过L1CAM介导的血管选择性逃避凋亡，各种其他因素如STAT3、PI3K、S6GALNAC5和组织蛋白酶S帮助这些细胞定植和生长。这些细胞还将其代谢调节为高OXPHOS，并变得较少糖酵解。

2. 与各种免疫疗法在治疗脑转移瘤中的意义相关的时间轴进展。

图2. 脑转移与肿瘤免疫治疗

1.  除了转移的肿瘤细胞外，脑转移瘤的肿瘤微环境(TME)包括独特的细胞类型，包括星形胶质细胞/活化星形胶质细胞、小胶质细胞、髓系抑制细胞(MDSCs)和神经元。星形胶质细胞/小胶质细胞释放的神经分泌物支持了脑转移的癌细胞在脑微环境中的生长。脑转移癌细胞有多种机制可以逃避免疫细胞的攻击，可能通过在癌细胞/免疫细胞中上调PD-L1/PD-1轴、过表达CD44等细胞表面受体，或通过分泌外泌体或其他代谢产物增强免疫抑制性调节T细胞（Treg）的招募。

2.  目前正在评估用于脑转移瘤治疗的各种免疫治疗，包括抗PD-L1/抗PD-1和抗CTLA4。免疫治疗增强T效应细胞（CD8+）的活性，或诱导肿瘤抗原呈递，从而引起免疫激活，促进癌细胞死亡。

表1. 免疫疗法治疗脑转移和软脑膜转移

表2. 治疗脑转移瘤中使用的各种癌症类型的关键免疫治疗药物

图3.目前临床上的不同免疫疗法及其在治疗脑转移中的应用

脑转移发生在癌症细胞从其原发肿瘤部位（通常是从乳腺、肺、肾/肾、结肠和黑色素瘤）迁移到大脑。图中显示的免疫疗法是在临床上结合放疗（RT）/立体定向放射外科（SRS）治疗脑转移。除了目前的ITs外，抗体-药物偶联物（ADC）和CART细胞的应用也可以用来提高这些治疗模式治疗BrM的疗效。

图4. 肿瘤微环境的代谢环境及其对免疫治疗或T细胞功能的影响

1.  Metabolic struggle and/ or metabolic reprogramming transpire between various tumor-infiltrating immune cells and tumor cells. Both T cells and tumor cells preferentially utilize glucose to meet their energy demands. Due to high proliferation potential and high energy needs, tumor cells metabolize most of the glucose through aerobic glycolysis and produce high levels of lactic acid (lactate) in the TME, thereby, decreasing glucose availability for immune cells. The lactate-enriched and glucose-deprived TME impairs T cell functioning, recruits more (regulatory T cells) Tregs, and polarizes microglial cells towards a protumorigenic phenotype and tumor-associated macrophages (TAMs). There is further competition for amino acids, including glutamine/glutamate and tryptophan between T cells, myeloid-derived suppressor cells (MDSCs), and tumor cells. The availability of these amino acids in the TME that modulate T cell-mediated immune response, such as kynurenine (a product of tryptophan catabolism) produced by indoleamine 2,3-dioxygenase 1 (IDO1) present in tumor cells, MDSCs, and TAMs blocks activation of T cells and promotes the recruitment and production of immunosuppressive Treg cells. The brain microenvironment has high glutamine and tryptophan; therefore, tumor cells easily adapt to the brain microenvironment utilizes these amino acids for their growth and development. Lactate production in the TME also increases the expression of PD-1 on T cells and PD-L1 on tumor cells and suppresses the activity of immune cells.

2. The immunotherapeutic response of ITs could be enhanced by targeting the various metabolic regulators of tumor cells and immune cells. The utilization of inhibitors that specifically target glucose transporters (GLUT1), lactate production, IDO1 activity, and glutamine utilization in tumor cells could be a potential therapeutic strategy to enhance the efficacies of ITs in brain metastasis

参考文献

Ahmad et al. Molecular Cancer (2023) 22:111