Zhu Yanli, Wu Jianghua, Wang Haiyue, Chi Kaiwen, Diao Xinting, Zhuo Minglei, Lin Dongmei
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department I of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
Transl Lung Cancer Res. 2025 Feb 28;14(2):449-466. doi: 10.21037/tlcr-24-924. Epub 2025 Feb 27.
The molecular subtype-specific features of the tumor immune microenvironment (TIME) in small cell lung carcinoma (SCLC) remain poorly understood. We aimed to analyze the immune profiles in surgically resected SCLC and their associations with molecular subtypes.
Tumor samples from 83 treatment-naive SCLC patients who underwent surgical resection were analyzed. The protein expression of subtype-defining markers (ASCL1, NEUROD1, POU2F3, and YAP1) and nine immune-related markers were assessed using whole-section immunohistochemistry. Digital image analysis was employed for precise quantification of immune cell infiltrates and distributions. The findings were subsequently correlated with clinicopathological parameters and patient prognoses.
Unsupervised hierarchical clustering categorized the tumors into four molecular subtypes: achaete-scute homologue 1-dominant (ASCL1; SCLC-A, 71.1%, n=59), neuronal differentiation factor 1-dominant (NEUROD1; SCLC-N, 12.1%, n=10), POU class 2 homeobox 3-dominant (POU2F3; SCLC-P, 10.8%, n=9), and quadruple-negative (SCLC-QN, 6.0%, n=5). Expression of major histocompatibility complex class I (MHC I) and class II (MHC II; P=0.02, P=0.02), tumor programmed death-ligand 1 (PD-L1; P=0.006), and an inflamed phenotype characterized by CD8/CD3 T cells (P=0.001, P=0.003) were more prominent in SCLC-P tumors compared to other subtypes. Additionally, SCLC-P tumors demonstrated the highest levels of MHC II (P=0.04) and PD-L1 expression on both tumor and stromal cells (P=0.003, P=0.01). The tumor proportion score of PD-L1 positively correlated with tumor expression levels of POU2F3 (rho=0.297, P=0.006) and MHC I (rho=0.239, P=0.03), as well as the combined positive score of PD-L1 (rho=0.222, P=0.04; rho=0.433, P<0.001). Intra-tumoral tertiary lymphoid structures (intra-TLS) and peri-tumoral TLS (peri-TLS) were observed in 60.2% (n=50) and 96.4% (n=80) of patients, respectively. High intra-TLS density was more frequently associated with SCLC-P tumors (P=0.02). Notably, low peri-TLS density and stromal PD-L1 expression were linked to improved overall survival (OS) and progression-free survival (PFS), respectively.
This study highlights the heterogeneity of the TIME across molecular subtypes of SCLC. The SCLC-P subtype and MHC I expression may serve as predictive biomarkers for immunotherapy response, while peri-TLS density and stromal PD-L1 expression might serve as prognostic indicators in resected SCLC.
小细胞肺癌（SCLC）中肿瘤免疫微环境（TIME）的分子亚型特异性特征仍知之甚少。我们旨在分析手术切除的SCLC中的免疫特征及其与分子亚型的关联。
对83例未经治疗且接受手术切除的SCLC患者的肿瘤样本进行分析。使用全切片免疫组织化学评估亚型定义标志物（ASCL1、NEUROD1、POU2F3和YAP1）和9种免疫相关标志物的蛋白表达。采用数字图像分析对免疫细胞浸润和分布进行精确量化。随后将结果与临床病理参数和患者预后相关联。
无监督层次聚类将肿瘤分为四种分子亚型：achaete - scute同源物1主导型（ASCL1；SCLC - A，71.1%，n = 59）、神经分化因子1主导型（NEUROD1；SCLC - N，12.1%，n = 10）、POU2类同源盒3主导型（POU2F3；SCLC - P，10.8%，n = 9）和四阴性型（SCLC - QN，6.0%，n = 5）。与其他亚型相比，主要组织相容性复合体I类（MHC I）和II类（MHC II；P = 0.02，P = 0.02）、肿瘤程序性死亡配体1（PD - L1；P = 0.006）以及以CD8/CD3 T细胞为特征的炎症表型（P = 0.001，P = 0.003）在SCLC - P肿瘤中更为突出。此外，SCLC - P肿瘤在肿瘤细胞和基质细胞上均表现出最高水平的MHC II（P = 0.04）和PD - L1表达（P = 0.003，P = 0.01）。PD - L1的肿瘤比例评分与POU2F3（rho = 0.297，P = 0.006）和MHC I（rho = 0.239，P = 0.03）的肿瘤表达水平以及PD - L1的联合阳性评分呈正相关（rho = 0.222，P = 0.04；rho = 0.433，P < 0.001）。分别在60.2%（n = 50）和96.4%（n = 80）的患者中观察到瘤内三级淋巴结构（intra - TLS）和瘤周TLS（peri - TLS）。高intra - TLS密度更常与SCLC - P肿瘤相关（P = 0.02）。值得注意的是，低peri - TLS密度和基质PD - L与总生存期（OS）和无进展生存期（PFS）的改善分别相关。
本研究突出了SCLC分子亚型中TIME的异质性。SCLC - P亚型和MHC I表达可能作为免疫治疗反应的预测生物标志物，而peri - TLS密度和基质PD - L1表达可能作为切除的SCLC的预后指标。
