A Tumor Cornification and Immune-Infiltration-based Scheme for Anti-Pd-1 Plus Chemotherapy Response in Advanced Squamous Cell Lung Carcinoma

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

Med（2024）

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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 CD56bright 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 CD56bright 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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Key words

immunotherapy,squamous cell lung cancer,biomarker,tumor microenvironment,activated CD8+ T cells,CD56bright NK cells,RNA-seq,single-cell RNA-seq,cornification,PD-1

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【要点】：本研究提出了一种基于肿瘤角化和免疫浸润特征的新型分类方案（LICC），可预测晚期鳞状细胞肺癌患者对抗PD-1免疫疗法联合化疗的反应。

【方法】：通过对来自随机、多中心、phase 3试验ORIENT-12的349例LUSC样本进行高通量RNA测序（RNA-seq），发现生物标志物，并通过流式细胞术、多重免疫组化（mIHC）以及体外实验进行验证。

【实验】：实验利用了ORIENT-12试验的数据，通过单细胞RNA测序分析，确定肿瘤角化信号主要映射到SPRR3+肿瘤细胞，并通过流式细胞术和mIHC验证了其与活化的CD8+T或CD56bright NK细胞的关系。结果显示，LICC1和LICC2亚型的患者在接受联合治疗后，无进展生存期（PFS）有显著改善。