A tumor cornification and immune-infiltration-based scheme for anti-PD-1 plus chemotherapy response in advanced squamous cell lung carcinoma.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Med Pub Date : 2024-10-11 DOI:10.1016/j.medj.2024.09.005

Minlin Jiang, Jiya Sun, Congli Hu, Lin Wu, Yun Fan, Zhehai Wang, Lianke Liu, Chunyan Wu, Fengying Wu, Guanghui Gao, Fei Li, Lei Wang, Xuefei Li, Lei Cheng, Bo Peng, Hui Zhou, Caicun Zhou

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Abstract

Background: Anti-PD-1 immunotherapy plus chemotherapy (combo) exhibits significantly prolonged survival for squamous cell lung cancer (LUSC). An exploration of predictive biomarkers is still needed.

Methods: High-throughput RNA sequencing (RNA-seq) of 349 LUSC samples from the randomized, multi-center, phase 3 trial ORIENT-12 (ClinicalTrials.gov: NCT03629925) was conducted for biomarker discovery, followed by flow cytometry and multiplex immunohistochemistry (mIHC) in additional clinical cohorts, and in vitro experiments were performed for verification.

Results: A high abundance of activated CD8⁺ T and CD56^bright natural killer (NK) cells benefited patients' outcomes (progression-free survival [PFS]; overall survival [OS]) with combo treatment. Tumor cornification level remarkably affected the infiltration of the two crucial immune cells. Thus, a novel scheme of LUSC immune infiltration and cornification characterization-based classification (LICC) was established for combo efficacy prediction. Patients who received combo treatment achieved significant PFS improvements in LICC1 (hazard ratio [HR] = 0.43, 95% confidence interval [CI]: 0.25-0.75, p = 0.0029) and LICC2 (HR = 0.32, 95% CI: 0.17-0.58, p = 0.0002) subtypes but not in the LICC3 subtype (HR = 0.86, 95% CI: 0.60-1.23, p = 0.4053). Via single-cell RNA-seq analysis, the tumor cornification signal was mainly mapped to SPRR3⁺ tumor cells, whose relationships with activated CD8⁺ T or CD56^bright NK cells were verified using flow cytometry and mIHC. Our data suggest that SPRR3⁺ tumor cells might evade immune surveillance via the CD24-SIGLEC10 (M2 macrophage) axis to maintain a suppressive tumor microenvironment.

Conclusions: Tumor cornification greatly impacts immune infiltration, and the LICC scheme may guide clinical medication of anti-PD-1+chemo treatment in patients with LUSC.

Funding: The study was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, Shanghia Multidisplinary Cooperation Building Project for Diagnosis and Treatment of Major Disease, and Innovent Biologics, Inc.

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晚期鳞状细胞肺癌抗 PD-1 加化疗反应的肿瘤粟粒化和免疫渗透方案。

背景抗PD-1免疫疗法加化疗（combo）可明显延长鳞状细胞肺癌（LUSC）患者的生存期。方法：对来自随机、多中心、三期试验 ORIENT-12 （ClinicalTrials.gov：NCT03629925）的 349 份 LUSC 样本进行高通量 RNA 测序（RNA-seq），以发现生物标志物，随后在其他临床队列中采用流式细胞术和多重免疫组化（mIHC），并进行体外实验进行验证：结果：活化的 CD8+ T 细胞和 CD56bright 自然杀伤（NK）细胞的高丰度有利于联合治疗后患者的预后（无进展生存期 [PFS]；总生存期 [OS]）。肿瘤粟粒化水平显著影响这两种关键免疫细胞的浸润。因此，我们建立了一种基于LUSC免疫浸润和粟粒化特征分类（LICC）的新方案，用于预测联合疗法的疗效。在LICC1中，接受联合治疗的患者的PFS明显改善（危险比[HR] = 0.43，95%置信区间[CI]：0.25-0.75，P＜0.05）：0.25-0.75，p = 0.0029）和 LICC2（HR = 0.32，95% CI：0.17-0.58，p = 0.0002）亚型，但在 LICC3 亚型（HR = 0.86，95% CI：0.60-1.23，p = 0.4053）中没有改善。通过单细胞RNA-seq分析，肿瘤粟粒化信号主要映射到SPRR3+肿瘤细胞，流式细胞术和mIHC验证了这些细胞与活化的CD8+ T或CD56bright NK细胞的关系。我们的数据表明，SPRR3+肿瘤细胞可能通过CD24-SIGLEC10（M2巨噬细胞）轴逃避免疫监视，以维持抑制性肿瘤微环境：肿瘤粟粒化对免疫浸润有很大影响，LICC方案可指导LUSC患者抗PD-1+化疗的临床用药：该研究得到了国家重点研发计划、国家自然科学基金、上药集团重大疾病诊治合作建设项目和Innovent Biologics, Inc.的资助。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.