免疫治疗对小细胞肺癌患者的临床受益与肿瘤抗原提呈能力相关

SCI

30 May 2023

Clinical benefit from immunotherapy in patients with small cell lung cancer isassociated with tumor capacity for antigen presentation

（Journal of thoracic oncology；IF：20.121）

Rudin CM, Balli D, Lai WV, Richards AL, Nguyen E, Egger JV, Choudhury NJ, Sen T, Chow A, Poirier JT, Geese WJ, Hellmann MD, Forslund A. Clinical benefit from immunotherapy in patients with small cell lung cancer is associated with tumor capacity for antigen presentation. J Thorac Oncol. 2023 May 18:S1556-0864(23)00554-3. doi: 10.1016/j.jtho.2023.05.008. Epub ahead of print. PMID: 37210008.

Correspondence: Charles M. Rudin MD PhD ，Memorial Sloan Kettering Cancer Center ，1275 York Ave. New York, NY 10065 ，646-888-4527 ，rudinc@mskcc.org ，@charlesrudin 

Purpose 目的

A small percentage of patients with small cell lung cancer (SCLC) experience durable responses to immune checkpoint blockade (ICB). Defining determinants of immune response may nominate strategies to broaden the efficacy of immunotherapy in patients with SCLC. Prior studies have been limited by small numbers and/or concomitant chemotherapy administration.

一小部分小细胞肺癌（SCLC）患者对免疫检查点阻断（ICB）有持久反应。明确免疫反应的决定因素可能会提出增加SCLC患者免疫疗法疗效的策略。先前的研究受到数量少和/或伴随化疗药物施用的限制。

Methods 方法

CheckMate 032, a multicenter, open-label, phase 1/2 trial evaluating nivolumab alone or with ipilimumab in patients with previously treated advanced or metastatic solid tumors was the largest study of ICB alone in patients with SCLC. We performed comprehensive RNA sequencing of 286 pretreatment SCLC tumor samples from patients enrolled on this study. We evaluated outcome based on defined SCLC subtypes (SCLC-A, -N, -P, and -Y), and explored expression signatures associated with durable benefit, defined as progression-free survival ≥ 6 months. Potential biomarkers were further explored by immunohistochemistry.

CheckMate 032是一项多中心、开放、I/II期试验，用于评估单用纳武单抗或与伊匹单抗联合治疗既往接受过治疗的晚期或转移性实体瘤患者，是对SCLC患者单独进行免疫检查点阻断（ICB）的最大研究。我们对参与本研究的286名患者的预处理SCLC肿瘤样本进行了全面的RNA测序。我们根据定义的SCLC亚型（SCLC-A、-N、-P和-Y）评估了结果，并探讨了与持久获益相关的表达印记，定义为无进展生存期≥6个月。通过免疫组织化学进一步探索潜在的生物标志物。

Results 结果

None of the subtypes were associated with progression-free or overall survival. YAP1 gene expression across the dataset was associated with an inflammation signature (R=0.25, p=0.00014), and SCLC-Y associated with expression of antigen presentation machinery (APM) (p<0.00001). The APM signature (p=0.000032) and presence of ≥ 1% infiltrating CD8+ T cells by immunohistochemistry (HR 0.51; 95% confidence interval 0.27 – 0.95) both correlated with overall survival in patients treated with nivolumab. Pathway enrichment analysis demonstrated association between durable benefit from immunotherapy and antigen processing and presentation. 

没有一种亚型与无进展生存期或总生存期相关。整个数据集的YAP1基因表达与炎症特征相关（R=0.25，p=0.000014），SCLC-Y与抗原呈递机制（APM）的表达相关（p<0.00001）。APM特征（p=0.0000032）和≥1%的通过免疫组织化学浸润的CD8+T细胞的存在（HR 0.51；95% 置信区间0.27–0.95）均与接受纳武单抗治疗患者的总生存期相关。通路富集分析表明，免疫疗法的持久受益与抗原处理和呈递之间存在关联。

Conclusions 结论

Tumor antigen processing and presentation is a key correlate of ICB efficacy in patients with SCLC. As antigen presentation machinery is frequently epigenetically suppressed in SCLC, this study defines a targetable mechanism by which we might improve clinical benefit of ICB for patients with SCLC. 

肿瘤抗原处理和呈递是SCLC患者免疫检查点阻断（ICB）疗效的关键相关因素。由于SCLC中抗原呈递机制经常受到表观遗传学抑制，本研究确定了一种靶向机制，我们可以通过该机制提高SCLC患者免疫检查点阻断（ICB）的临床受益。

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