Department of Radiotherapy, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
College of Computer and Information Engineering, Nanjing Tech University, Nanjing, Jiangsu, China.
Front Immunol. 2024 Oct 15;15:1430163. doi: 10.3389/fimmu.2024.1430163. eCollection 2024.
Lung adenocarcinoma, a prevalent and lethal malignancy globally, is characterized by significant tumor heterogeneity and a complex tumor immune microenvironment during its histologic pattern progression. Understanding the intricate interplay between tumor and immune cells is of paramount importance as it could potentially pave the way for the development of effective therapeutic strategies for lung adenocarcinoma.
In this study, we run comparative analysis of the single-cell transcriptomic data derived from tumor tissues exhibiting four distinct histologic patterns, lepidic, papillary, acinar and solid, in lung adenocarcinoma. Furthermore, we conducted immunofluorescence assay and spatial transcriptomic sequencing to validated the spatial co-localization of typical co-inhibitory factors.
Our analysis unveiled several co-inhibitory receptor-ligand interactions, including PD1-PDL1, PVR-TIGIT and TIGIT-NECTIN2, that potentially exert a pivotal role in recruiting immunosuppressive cells such as M2 macrophages and Tregs into LUAD tumor, thereby establishing immunosuppressive microenvironment and inducing T cells to exhaustion state. Furthermore, The expression level of these co-inhibitory factors, such as NECTIN2 and PVR, were strongly correlated with low immune infiltration, unfavorable patient clinical outcomes and limited efficacy of immunotherapy. We believe this study provides valuable insights into the heterogeneity of molecular, cellular interactions leading to immunosuppressive microenvironment during the histological progression of lung adenocarcinoma. The findings could facilitate the development of novel immunotherapy for lung cancer.
肺腺癌是一种全球范围内普遍存在且致命的恶性肿瘤，其特征是在组织学模式进展过程中存在显著的肿瘤异质性和复杂的肿瘤免疫微环境。了解肿瘤细胞和免疫细胞之间的复杂相互作用至关重要，因为它可能为肺腺癌的有效治疗策略的发展铺平道路。
在这项研究中，我们对源自肺腺癌中表现出四种不同组织学模式（贴壁状、乳头状、腺泡状和实体状）的肿瘤组织的单细胞转录组数据进行了比较分析。此外，我们进行了免疫荧光分析和空间转录组测序，以验证典型共抑制因子的空间共定位。
我们的分析揭示了几种共抑制受体-配体相互作用，包括 PD1-PDL1、PVR-TIGIT 和 TIGIT-NECTIN2，它们可能在招募免疫抑制细胞（如 M2 巨噬细胞和 Tregs）进入 LUAD 肿瘤中发挥关键作用，从而建立免疫抑制微环境并诱导 T 细胞衰竭状态。此外，这些共抑制因子（如 NECTIN2 和 PVR）的表达水平与免疫浸润低、患者临床结局不良和免疫治疗效果有限密切相关。我们相信这项研究为肺腺癌组织学进展过程中导致免疫抑制微环境的分子和细胞相互作用的异质性提供了有价值的见解。这些发现可能有助于开发针对肺癌的新型免疫疗法。
