Blockade of Adenosine-driven Immune Suppression in Brain Metastasis to Overcome Resistance against Immunotherapy

脑转移瘤(BRM)是一种尚未得到满足的临床需求，需要新的有效的治疗策略来改善BRM患者的治疗选择和生活质量。鉴于肿瘤相关间质和免疫细胞在疾病进展中的关键作用，肿瘤微环境(TME)靶向治疗的益处日益得到认可，阻断肿瘤促进功能或支持抗肿瘤免疫的策略正在涌现。BRM中的TME的特点是髓系细胞含量高，T细胞浸润程度低至中等，取决于原发肿瘤实体。主要由单核细胞来源的巨噬细胞介导的BRM中强烈的免疫抑制环境常常削弱T细胞定向免疫治疗的疗效。转录分析显示，在BRM的免疫和肿瘤细胞中诱导了嘌呤组分，这表明腺苷能信号在免疫抑制和T细胞耗竭中起着关键作用。我们使用遗传和药理学策略来靶向嘌呤体体的不同成分，将腺苷介导的免疫抑制转化为嘌呤驱动的炎症，从而为BRM中有效的T细胞重新激活创造了环境。我们的数据证实了腺苷能信号在抑制BRM抗肿瘤免疫反应中的中心作用。这种作用可以通过药物抑制核苷酸酶CD39和CD73以及腺苷受体A2a来取消。全脑放射治疗(WBRT)的额外应用进一步提高了中位生存期，而单独应用aPD1或与WBRT联合应用在腺苷能信号阻断的情况下并没有显示出有益的效果。综上所述，阻断代谢免疫检查点结合放射治疗是控制BRM疾病进展的一种很有前途的策略。然而，需要更多的洞察力来进一步改进策略，通过在阻断腺苷能信号的背景下抑制免疫检查点来有效地重新激活T细胞反应。在这里，我们建议进行详细的分析如何在嘌呤组的变化调节免疫状态在BRM。我们试图将这些发现转化为改进的干预策略，以期克服限制免疫治疗对BRM疗效的组织特异性耐药机制。

Brain metastasis (BrM) represents an unmet clinical need with high demand for novel and effective therapeutic strategies to improve treatment options and quality of life for BrM patients. Given the critical role of tumor-associated stromal and immune cells in disease progression, benefits of tumor microenvironment (TME)-targeted therapies are increasingly recognized and strategies that block tumor-promoting functions or support anti-tumor immunity are emerging. The TME in BrM is characterized by high myeloid cell content and low to moderate T cell infiltration depending on the primary tumor entity. Therapeutic efficacy of T cell-directed immunotherapy is often blunted by the strong immune suppressive milieu in BrM predominantly mediated by monocyte-derived macrophages. Transcriptomic analyses revealed an induction of components of the purinome in immune and tumor cells in BrM suggesting a critical role of adenosinergic signaling in immune suppression and T cell exhaustion. We employed genetic and pharmacological strategies to target different components of the purinome to convert adenosine-mediated immune-suppression into purine-driven inflammation thereby creating an environment for effective T cell reactivation in BrM. Our data confirmed a central role of adenosinergic signaling in suppressing anti-tumor immune responses in BrM. This effect could be revoked by pharmacological inhibition of the nucleotidases CD39 and CD73 as well as the adenosine receptor A2a. Additional application of whole brain radiotherapy (WBRT) further improved median survival, while the addition of aPD1 alone or in combination with WBRT did not show beneficial effects in the context of adenosinergic signaling blockade. Taken together, blockade of metabolic immune checkpoints combined with radiotherapy represents a promising strategy to control disease progression in BrM. However, additional insight is needed to further improve strategies for effective reactivation of T cell responses by immune checkpoint inhibition in the context of blockade of adenosinergic signaling. Here, we propose to perform detailed analyses how changes in the purinome modulate the immune status in BrM. We seek to translate these findings into improved intervention strategies with the aim to overcome tissue-specific resistance mechanisms that limit the efficacy of immunotherapy against BrM.