De Rosa Caterina, Iommelli Francesca, De Rosa Viviana, Ercolano Giuseppe, Sodano Federica, Tuccillo Concetta, Amato Luisa, Tirino Virginia, Ariano Annalisa, Cimmino Flora, di Guida Gaetano, Filosa Gennaro, di Liello Alessandra, Ciardiello Davide, Martinelli Erika, Troiani Teresa, Napolitano Stefania, Martini Giulia, Ciardiello Fortunato, Papaccio Federica, Morgillo Floriana, Della Corte Carminia Maria
Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy.
Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy.
Biomedicines. 2024 Apr 5;12(4):809. doi: 10.3390/biomedicines12040809.
Lung cancer (LC), including both non-small (NSCLC) and small (SCLC) subtypes, is currently treated with a combination of chemo- and immunotherapy. However, predictive biomarkers to identify high-risk patients are needed. Here, we explore the role of peripheral blood mononuclear cells (PBMCs) as a tool for novel biomarkers searching.
We analyzed the expression of the cGAS-STING pathway, a key DNA sensor that activates during chemotherapy, in PBMCs from LC patients divided into best responders (BR), responders (R) and non-responders (NR). The PBMCs were whole exome sequenced (WES).
PBMCs from BR and R patients of LC cohorts showed the highest levels of STING ( < 0.0001) and CXCL10 ( < 0.0001). From WES, each subject had at least 1 germline/somatic alteration in a DDR gene and the presence of more DDR gene mutations correlated with clinical responses, suggesting novel biomarker implications. Thus, we tested the effect of the pharmacological DDR inhibitor (DDRi) in PBMCs and in three-dimensional spheroid co-culture of PBMCs and LC cell lines; we found that DDRi strongly increased cGAS-STING expression and tumor infiltration ability of immune cells in NR and R patients. Furthermore, we performed FACS analysis of PBMCs derived from LC patients from the BR, R and NR cohorts and we found that cytotoxic T cell subpopulations displayed the highest STING expression.
cGAS-STING signaling activation in PBMCs may be a novel potential predictive biomarker for the response to immunotherapy and high levels are correlated with a better response to treatment along with an overall increased antitumor immune injury.
肺癌（LC）包括非小细胞肺癌（NSCLC）和小细胞肺癌（SCLC）亚型，目前采用化疗和免疫治疗联合方案。然而，需要预测生物标志物来识别高危患者。在此，我们探讨外周血单个核细胞（PBMCs）作为寻找新型生物标志物工具的作用。
我们分析了cGAS-STING通路的表达，这是一种在化疗期间激活的关键DNA传感器，在分为最佳反应者（BR）、反应者（R）和无反应者（NR）的LC患者的PBMCs中进行分析。对PBMCs进行了全外显子测序（WES）。
LC队列中BR和R患者的PBMCs显示出最高水平的STING（<0.0001）和CXCL10（<0.0001）。通过WES，每个受试者在DNA损伤修复（DDR）基因中至少有1个种系/体细胞改变，并且更多DDR基因突变的存在与临床反应相关，提示有新型生物标志物的意义。因此，我们测试了药理学DDR抑制剂（DDRi）对PBMCs以及PBMCs与LC细胞系的三维球体共培养的影响；我们发现DDRi强烈增加了NR和R患者免疫细胞的cGAS-STING表达和肿瘤浸润能力。此外，我们对来自BR、R和NR队列的LC患者的PBMCs进行了荧光激活细胞分选（FACS）分析，发现细胞毒性T细胞亚群显示出最高的STING表达。
PBMCs中cGAS-STING信号激活可能是免疫治疗反应的一种新型潜在预测生物标志物，高水平与更好的治疗反应以及整体抗肿瘤免疫损伤增加相关。
