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

阻断脑转移中腺苷驱动的免疫抑制以克服对免疫治疗的耐药性

• 批准号: 405993611
• 负责人: Professorin Dr. Lisa Sevenich, Ph.D.
• 金额: --
• 依托单位: Abteilung Neurologie mit Interdisziplinärem Schwerpunkt Neuroonkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/405993611?language=en
• 关键词: Blockade; Adenosine; driven; Immune; Suppression

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.

脑转移（BrM）代表了一种未满足的临床需求，对新型有效的治疗策略有很高的需求，以改善BrM患者的治疗选择和生活质量。鉴于肿瘤相关基质细胞和免疫细胞在疾病进展中的关键作用，肿瘤微环境（TME）靶向治疗的益处越来越受到认可，并且正在出现阻断肿瘤促进功能或支持抗肿瘤免疫的策略。BrM中的TME的特征在于高骨髓细胞含量和低至中度T细胞浸润，这取决于原发性肿瘤实体。T细胞导向的免疫疗法的治疗功效通常被主要由单核细胞衍生的巨噬细胞介导的BrM中的强免疫抑制环境减弱。转录组学分析显示，在免疫和肿瘤细胞中的嘌呤组的成分在BrM的诱导，这表明在免疫抑制和T细胞耗竭的腺苷能信号转导的关键作用。我们采用遗传和药理学策略来靶向嘌呤组的不同成分，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细胞再激活创造环境。我们的数据证实了腺苷能信号传导在抑制BrM中的抗肿瘤免疫应答中的核心作用。这种作用可以通过对核苷酸酶CD 39和CD 73以及腺苷受体A2a的药理学抑制来撤销。额外应用全脑放疗（WBRT）进一步改善了中位生存期，而单独添加aPD 1或与WBRT联合使用在腺苷能信号传导阻断的背景下未显示出有益效果。总之，代谢免疫检查点的阻断与放射治疗相结合代表了控制BrM疾病进展的有希望的策略。然而，需要更多的见解来进一步改善在腺苷能信号传导阻断的背景下通过免疫检查点抑制有效再激活T细胞应答的策略。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BrM的免疫状态。我们试图将这些发现转化为改进的干预策略，旨在克服限制针对BrM的免疫疗法疗效的组织特异性耐药机制。