Kozakov Denys, Kobyliak Nazarii, Livshun Sofiia, Seleznov Oleksii, Koshyk Olena, Matvieieva Alina, Shparyk Yaroslav, Kolesnik Oleksii, Moskalenko Yuliia, Vynnychenko Oleksandr, Moskalenko Roman, Kropyvko Serhii, Khmel Anna, Shkarupii Bogdana, Sulaieva Oksana
Medical Laboratory CSD, Kyiv, Ukraine.
Institute of Molecular Biology and Genetics NASU, Kyiv, Ukraine.
Front Med (Lausanne). 2025 Jul 30;12:1558016. doi: 10.3389/fmed.2025.1558016. eCollection 2025.
Although the role of various genetic alterations was highlighted among factors affecting the response to immunotherapy in non-small cell lung cancer (NSCLC), the relations between oncogenic driver variants and changes in the cancer immunity cycle are still unclear.
The study aimed to discover the links between the molecular and immune context of NSCLC.
This cohort study included 254 cases of NSCLC (193 Lung Adenocarcinomas) (LUAD; 76%), and 61 squamous cell carcinomas (SCC; 24%), with pathology reports and next-generation sequencing (NGS) data available. First, the rate and spectrum of genetic alterations were assessed in the Ukrainian cohort. Second, we uncovered the relationship between the oncogenic driver mutations and PD-L1 expression in NSCLC. Finally, T-cytotoxic lymphocytes (CD8) and tumor-associated macrophages (CD163) were evaluated in samples with and mutations, rearrangements and LUAD with no genetic findings. Immune desert, immune excluded and inflamed types of tumor immune microenvironment (TME) were defined according to the cancer immunity cycle.
More than half (52%) of the observed NSCLC cases harbored single (48.03%) or concomitant (3.94%) genetic alterations in oncogenes. The Ukrainian cohort demonstrated a high rate of (18.5%) and rearrangements (9.4%) with a relatively moderate frequency of mutations (16.9%). NSCLC tumors with alterations in and demonstrated a high incidence of PD-L1 expression and specific immune contexture. The number of CD8 cells varied significantly between oncogene-driven and wild-type LUAD ( = 0.019). Non-oncogene-addicted NSCLC demonstrated the prevalence of Inflamed TME rich in CD163 macrophages. In contrast, over half of mutant LUAD cases possessed immune desert TME type, while -rearranged and mutant NSCLC showed mostly immune excluded TME.
The high rate of PD-L1 expression in NSCLC driven by and alterations was accompanied by a prevalence of low immunogenicity with a shift toward ID TME in mutant tumors and IE TME in rearranged and mutant NSCLC. Further discovery of mechanisms affecting tumor immune contexture is needed for tailoring patient management in line with particular mechanisms of immune evasion.
尽管在影响非小细胞肺癌（NSCLC）免疫治疗反应的因素中，各种基因改变的作用受到了关注，但致癌驱动变异与癌症免疫循环变化之间的关系仍不清楚。
本研究旨在发现NSCLC分子背景与免疫背景之间的联系。
这项队列研究纳入了254例NSCLC病例（193例肺腺癌（LUAD；76%）和61例鳞状细胞癌（SCC；24%）），有病理报告和二代测序（NGS）数据。首先，评估乌克兰队列中基因改变的发生率和谱。其次，我们揭示了NSCLC中致癌驱动突变与PD-L1表达之间的关系。最后，在有和无 突变、 重排以及无基因改变的LUAD样本中评估细胞毒性T淋巴细胞（CD8）和肿瘤相关巨噬细胞（CD163）。根据癌症免疫循环定义免疫荒漠、免疫排除和炎症型肿瘤免疫微环境（TME）。
超过一半（52%）的观察到的NSCLC病例在癌基因中存在单个（48.03%）或伴随（3.94%）基因改变。乌克兰队列显示 （18.5%）和 重排（9.4%）的发生率较高， 突变频率相对适中（16.9%）。 改变和 改变的NSCLC肿瘤显示出较高的PD-L1表达发生率和特定的免疫特征。癌基因驱动的LUAD和野生型LUAD之间CD8细胞数量差异显著（ = 0.019）。非癌基因依赖型NSCLC显示富含CD163巨噬细胞的炎症型TME占优势。相比之下，超过一半的 突变LUAD病例具有免疫荒漠型TME，而 重排和 突变的NSCLC大多显示免疫排除型TME。
改变和 改变驱动的NSCLC中PD-L1高表达伴随着低免疫原性的普遍存在， 突变肿瘤向免疫荒漠型TME转变， 重排和 突变的NSCLC向免疫排除型TME转变。需要进一步发现影响肿瘤免疫特征的机制，以便根据特定的免疫逃逸机制调整患者管理。
