Molecular determinants of resistance to immune checkpoint blockade in melanoma brain metastases

PD-1和CTLA-4是免疫抑制受体（免疫检查点），主要在T细胞和NK细胞上表达。它们与功能阻断抗体的抑制作用增强了抗肿瘤反应，从而在包括黑色素瘤在内的不同癌症中产生了有希望的治疗效果。约60%的黑色素瘤患者发生脑转移（BrM），预后较差。最近的临床试验表明，与单一治疗相比，PD-1/CTLA-4 （P/C）联合阻断在黑色素瘤BrM中的活性更高。然而，约44%的患者对P/C阻断没有反应，需要进一步提高治疗效果。这需要对耐药性机制有更好的了解。使用小鼠黑色素瘤BrM模型，我们已经证明NK细胞在P/C阻断的颅内疗效中起关键作用（Taggart等人，2018）。我们进一步确定了从应答者和非应答者以及未经治疗的对照小鼠中分离的大肿瘤（BrM和皮肤肿瘤）和NK细胞的转录谱（mRNAseq）的差异。我们计划对这些临床前数据和公开可用的患者数据进行深入的生物信息学分析，以阐明BrM和颅外肿瘤中免疫检查点阻断（ICB）耐药的临床相关机制，并确定两者之间的潜在差异。

PD-1 and CTLA-4 are immune-inhibitory receptors (immune checkpoints) expressed mainly on T cells and NK cells. Their inhibition with function-blocking antibodies enhances anti-tumour responses, resulting in promising therapeutic efficacy in different cancers, including melanoma. ~60% of melanoma patients develop brain metastases (BrM), which are associated with poor prognosis. Recent clinical trials demonstrated a superior activity of combined PD-1/CTLA-4 (P/C) blockade in melanoma BrM as compared to the monotherapies. However, ~44% of patients fail to respond to P/C blockade, requiring further enhancement of the therapeutic efficacy. This requires a better understanding of the resistance mechanisms.Using mouse melanoma BrM models, we have demonstrated a critical role of NK cells in the intracranial efficacy of P/C blockade (Taggart et al., 2018). We further identified differences in the transcriptional profiles (mRNAseq) of bulk tumours (BrM and skin tumours) and NK cells isolated from responders versus non-responders, as well as untreated control mice. We plan to perform an in-depth bioinformatics analysis of these preclinical data and publicly available patient data to shed light on the clinically relevant mechanisms of resistance to immune checkpoint blockade (ICB) in BrM and extracranial tumours, and to identify potential differences between the two sites.