非小细胞肺癌的肿瘤微环境揭示了放化疗后PD-L1阻断的耐药机制:一项多中心前瞻性生物标志物研究

SCI

2 July 2023

Tumor microenvironment landscape of non–small cell lung cancer reveals resistance mechanisms for PD-L1 blockade following chemoradiotherapy: a multi-center prospective biomarker study

(Journal of Thoracic Oncology; IF:20.4)

Correspondence to:Koji Haratani, Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan. Tel.: +81-72-366-0221. Fax: +81-72-360-5000. Email: haratani_k@med.kindai.ac.jp

Haratani K, Nakamura A, Mamesaya N, et al. Tumor microenvironment landscape of non-small cell lung cancer reveals resistance mechanisms for PD-L1 blockade following chemoradiotherapy: a multi-center prospective biomarker study (WJOG11518L/SUBMARINE). J Thorac Oncol. 2023

Introduction 介绍

The PACIFIC regimen of consolidation therapy with the programmed cell death–ligand 1 (PD-L1) inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III non–small cell lung cancer (NSCLC). However, about half of treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L/SUBMARINE).

在确定的同步放化疗后，采用程序性细胞死亡配体1 (PD-L1)抑制剂durvalumab进行巩固治疗的PACIFIC方案已成为不可切除的III期非小细胞肺癌(NSCLC)患者的标准治疗方案。然而，大约一半接受治疗的患者在1年内出现疾病进展，对治疗耐药的机制知之甚少。我们在这里进行了一项全国范围的前瞻性生物标志物研究，以探索耐药机制(WJOG11518L/SUBMARINE)。

Methods 方法

A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue as well as flow cytometric analysis of circulating immune cells. Progression-free survival (PFS) was compared based on these biomarkers.

共纳入135例接受PACIFIC方案的不可切除III期NSCLC患者，通过免疫组化、转录组分析、预治疗肿瘤组织基因组测序以及循环免疫细胞流式细胞术分析，全面分析肿瘤微环境。基于这些生物标志物比较无进展生存期(PFS)。

Results 结果

The importance of preexisting effective adaptive immunity in tumors were revealed for treatment benefit regardless of genomic features. We also identified CD73-expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocytes (TILs) density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (HRs, 4.05 [95% CI, 1.17-14.04] for CD8+ TILs; 4.79 [95% CI, 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity.

无论基因组特征如何，肿瘤中预先存在的有效适应性免疫对治疗效果的重要性都得到了揭示。我们还发现癌细胞的CD73表达是对PACIFIC方案的一种抵抗机制。以关键临床因素为协变量的免疫组织化学数据的多变量分析表明，CD8+肿瘤浸润淋巴细胞(TILs)密度低和CD73+癌细胞高与durvalumab预后差独立相关(HR, 4.05 [95% CI, 1.17-14.04];CD73为4.79 [95% CI, 1.12-20.58])。此外，配对肿瘤样本的全外显子组测序表明，由于新抗原的可塑性，癌细胞最终逃脱了免疫压力。

Conclusions 结论

Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC, and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.

我们的研究强调了功能性适应性免疫在III期非小细胞肺癌中的重要性，并暗示CD73是一个有希望的治疗靶点，从而为开发新的非小细胞肺癌治疗方法提供了基础。

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