From the Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston (Parra, Jiang).
The Department of Pathology and Laboratory of Genomics and Histomorphometry (Machado-Rugolo, Yaegashi, Prieto, Farhat, de Sá, Capelozzi).
Arch Pathol Lab Med. 2020 Oct 1;144(10):1234-1244. doi: 10.5858/arpa.2019-0419-OA.
CONTEXT.—: Identification of gene mutations that are indicative of epithelial-mesenchymal transition and a noninflammatory immune phenotype may be important for predicting response to immune checkpoint inhibitors.
OBJECTIVE.—: To evaluate the utility of multiplex immunofluorescence for immune profiling and to determine the relationships among tumor immune checkpoint and epithelial-mesenchymal transition genomic profiles and the clinical outcomes of patients with nonmetastatic non-small cell lung cancer.
DESIGN.—: Tissue microarrays containing 164 primary tumor specimens from patients with stages I to IIIA non-small cell lung carcinoma were examined by multiplex immunofluorescence and image analysis to determine the expression of programmed death ligand-1 (PD-L1) on malignant cells, CD68+ macrophages, and cells expressing the immune markers CD3, CD8, CD57, CD45RO, FOXP3, PD-1, and CD20. Immune phenotype data were tested for correlations with clinicopathologic characteristics, somatic and germline genetic variants, and outcome.
RESULTS.—: A high percentage of PD-L1+ malignant cells was associated with clinicopathologic characteristics, and high density of CD3+PD-1+ T cells was associated with metastasis, suggesting that these phenotypes may be clinically useful to identify patients who will likely benefit from immunotherapy. We also found that ZEB2 mutations were a proxy for immunologic ignorance and immune tolerance microenvironments and may predict response to checkpoint inhibitors. A multivariate Cox regression model predicted a lower risk of death for patients with a high density of CD3+CD45RO+ memory T cells, carriers of allele G of CTLA4 variant rs231775, and those whose tumors do not have ZEB2 mutations.
CONCLUSIONS.—: Genetic variants in epithelial-mesenchymal transition and immune checkpoint genes are associated with immune cell profiles and may predict patient outcomes and response to immune checkpoint blockade.
识别上皮-间质转化和非炎症免疫表型的基因突变对于预测免疫检查点抑制剂的反应可能很重要。
评估多重免疫荧光在免疫分析中的应用，并确定肿瘤免疫检查点和上皮-间质转化基因组谱与非转移性非小细胞肺癌患者临床结局之间的关系。
通过多重免疫荧光和图像分析检测包含 164 例 I 期至 IIIA 期非小细胞肺癌患者的组织微阵列，以确定恶性细胞、CD68+巨噬细胞和表达免疫标志物 CD3、CD8、CD57、CD45RO、FOXP3、PD-1 和 CD20 的细胞上程序性死亡配体-1（PD-L1）的表达。对免疫表型数据进行检测，以确定与临床病理特征、体细胞和种系遗传变异以及结局的相关性。
高比例的 PD-L1+恶性细胞与临床病理特征相关，而 CD3+PD-1+T 细胞的高密度与转移相关，这表明这些表型可能在临床上有助于识别可能受益于免疫治疗的患者。我们还发现 ZEB2 突变是免疫忽视和免疫耐受微环境的代表，可能预测对检查点抑制剂的反应。多变量 Cox 回归模型预测高密度 CD3+CD45RO+记忆 T 细胞、CTLA4 变体 rs231775 等位基因 G 的携带者以及肿瘤无 ZEB2 突变的患者死亡风险较低。
上皮-间质转化和免疫检查点基因的遗传变异与免疫细胞谱相关，可能预测患者结局和对免疫检查点阻断的反应。
