支链氨基酸代谢影响肺癌免疫检查点阻断治疗疗效的机制探索

Immune checkpoint blockade therapy has achieved great success in the treatment of lung cancer. However, clinical studies have shown that only 20% of patients benefit from immunotherapy. Recent studies indicate that a variety of factors are associated with the efficacy of immune checkpoint blockade treatment, such as programmed cell death-ligand 1(PD-L1) expression levels in tumor tissues and tumor mutation burden. Benefit from ongoing clinical trials of anti-PD-1 /anti-PD-L1 treatment in patients with lung cancer, we have analyzed the metabolomics characteristics in periphery of the patients.It was obvious that patients with good efficacy had higher levels of branched-chain amino acids (BCAAs) than those with poor efficacy. Since BCAA is reported to be involved in the immune regulation, we thus hypothesized that the altheration of BCAA in patients with good efficacy might be due to the enhancement of T cell functionality. Accordingly, we will investigate on the roles of BCCAs in immune checkpoint therapy for lung cancer. First of all, we will clarify the effects of BCAAs on anti-PD-L1 therapy by using animal experiments. Secondly, we will analyze the effects of BCAAs on T-cell functionity and the underlying mechanism during immune checkpoint therapy. Finally, we will elucidate the metabolic pathways in T cells that BCAA is involved. Our results will probably provide a theoretical basis for the effects of BCAA on the efficacy of anti-PD-L1 therapy and lay a foundation for improving the efficacy of anti-PD-L1 therapy from the viewpoint of BCAA nutrition.

免疫检查点阻断治疗在肺癌治疗中疗效显著，然而临床结果示仅20%患者可从中获益。现已发现多种因素与其疗效相关，如肿瘤组织PD-L1表达、肿瘤基因突变载荷等。我们前期利用临床正开展的PD-1/PD-L1肺癌研究，同步分析患者外周代谢组学特征，结果显示疗效好的患者血浆中支链氨基酸（BCAA）水平显著高于疗效不佳组，表明BCAA水平与抗PD-L1疗效具正相关性。BCAA作为人体必需氨基酸，是否通过对T细胞免疫应答的调节，进而影响肺癌免疫检查点治疗疗效值得深入研究。为此，我们将围绕“BCAA如何影响免疫检查点治疗肺癌疗效”的科学问题，利用动物实验明确BCAA影响抗PD-L1疗效的机制，并进一步解析BCAA参与调节免疫检查点治疗过程中对T细胞功能的作用，获得其参与调节T细胞功能的能量途径，为BCAA参与抗PD-L1治疗疗效提供免疫学理论依据，该成果有望为从BCAA营养角度提高抗PD-L1疗效奠定基础。

支链氨基酸（BCAAs）是一类具有支链碳骨架的必需氨基酸，包括亮氨酸、异亮氨酸和缬氨酸，是合成蛋白质的主要来源。研究发现BCAAs代谢参与对免疫细胞的功能调节，在肿瘤等疾病中发挥重要作用，但其对肺癌免疫治疗的影响尚无报道。本研究发现抗PD-1治疗晚期非小细胞肺癌（NSCLC）响应组患者血浆BCAAs水平显著高于非响应组，并且和更好的无疾病进展期（PFS）相关。本项目进一步探索BCAAs促进免疫治疗响应的免疫学机制。研究发现PP2Cm（参与BCAAs代谢调控的关键酶）基因敲除小鼠的CD8+T细胞展示出更强的细胞因子表达能力和肿瘤细胞杀伤活性，并且可以显著抑制肿瘤细胞在小鼠体内的增殖。伴随着mTOR-PI3K-AKT-FoxO1信号通路的激活，PP2Cm-/- CD8+T 细胞上葡萄糖转运蛋白（Glut1）表达上调，葡萄糖转运增加，细胞氧化磷酸化水平增强。更重要的发现是添加BCAAs可以促进CD8+T细胞葡萄糖的氧化磷酸化，增强细胞的肿瘤细胞杀伤能力，促进抗PD-1治疗肺癌的效果。本研究为BCAAs促进抗PD-1治疗疗效提供免疫学理论依据，有望为从BCAAs营养角度提高抗PD-1疗效奠定基础。