Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA.
Lung Cancer. 2022 Oct;172:19-28. doi: 10.1016/j.lungcan.2022.08.007. Epub 2022 Aug 10.
Pathologists have routinely observed distinct histologic patterns of growth in early-stage lung adenocarcinoma (LUAD), which have been suggested to be associated with prognosis. Herein, we investigated the relationship between LUAD patterns of growth, as defined by the updated international association for the study of lung cancer (IASLC) grading criteria, and differences in the tumor immune microenvironment to identify predictors of response to immunotherapy.
174 resected stage I-III LUAD tumors were classified by histologic pattern of growth (i.e. solid, micropapillary, acinar, papillary, and lepidic) and then grouped as well differentiated, moderately differentiated, and poorly differentiated. Comprehensive multiplatform analysis including whole exome sequencing, gene expression profiling, immunohistochemistry, CIBERSORT, and T-cell receptor sequencing was performed and groups were compared for differences in genomic drivers, immune cell infiltrate, clonality, and survival. Finally, multivariate analysis was performed adjusting for pathologic stage and smoking status.
Poorly differentiated tumors demonstrated a strong association with smoking relative to moderately differentiated or well differentiated tumors. However, unlike in prior reports, poorly differentiated tumors were not associated with a worse survival after curative-intent resection. Genomic analysis revealed that poorly differentiated tumors are associated with high tumor mutation burden but showed no association with oncogenic drivers. Immune analyses revealed that poorly differentiated tumors are associated with increased T-cell clonality, expression of PD-L1, and infiltration by cytotoxic CD8 T-cells, activated CD4 T-cells, and pro-inflammatory (M1) macrophages. Finally, multivariate analysis controlling for stage and smoking status confirmed independence of immune differences between IASLC grade groups.
Poorly differentiated tumors, as defined by the updated IASLC grading criteria, are associated with a distinct immunogenic tumor microenvironment that predicts for therapeutic response to immune agents, including checkpoint inhibitors, and should be included in the clinical trial design of immunotherapy studies in early-stage lung adenocarcinoma.
病理学家已经观察到早期肺腺癌（LUAD）中明显不同的生长组织学模式，这些模式与预后有关。在此，我们研究了 LUAD 生长模式（由国际肺癌研究协会（IASLC）更新的分级标准定义）与肿瘤免疫微环境之间的关系，以确定免疫治疗反应的预测因子。
对 174 例 I 期至 III 期 LUAD 肿瘤进行组织学生长模式（即实性、微乳头状、腺泡状、乳头状和贴壁状）分类，然后分为高分化、中分化和低分化。进行全面的多平台分析，包括全外显子测序、基因表达谱分析、免疫组化、CIBERSORT 和 T 细胞受体测序，并比较组间在基因组驱动因素、免疫细胞浸润、克隆性和生存方面的差异。最后，进行多变量分析，调整病理分期和吸烟状态。
低分化肿瘤与中分化或高分化肿瘤相比，与吸烟有很强的关联。然而，与之前的报道不同，低分化肿瘤在根治性切除后与生存率下降无关。基因组分析显示，低分化肿瘤与高肿瘤突变负担有关，但与致癌驱动因素无关。免疫分析显示，低分化肿瘤与 T 细胞克隆性增加、PD-L1 表达以及细胞毒性 CD8 T 细胞、活化 CD4 T 细胞和促炎（M1）巨噬细胞浸润有关。最后，多变量分析控制了分期和吸烟状况，证实了 IASLC 分级组之间免疫差异的独立性。
根据 IASLC 更新的分级标准，低分化肿瘤与独特的免疫原性肿瘤微环境有关，预测对免疫治疗药物（包括检查点抑制剂）的治疗反应，在早期肺腺癌的免疫治疗研究的临床试验设计中应包括低分化肿瘤。
