Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.
Department of Medical Oncology and.
JCI Insight. 2016 Sep 8;1(14):e89014. doi: 10.1172/jci.insight.89014.
Immune checkpoint blockade improves survival in a subset of patients with non-small-cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. We performed comprehensive flow cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next-generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC). Cytometric profiling identified an immunologically "hot" cluster with abundant CD8 T cells expressing high levels of PD-1 and TIM-3 and an immunologically "cold" cluster with lower relative abundance of CD8 T cells and expression of inhibitory markers. The "hot" cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the "hot" cluster. Additionally, approximately 20% of cases had high B cell infiltrates with a subset producing IL-10. Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer. The Robert A. and Renée E. Belfer Family Foundation, Expect Miracles Foundation, Starr Cancer Consortium, Stand Up to Cancer Foundation, Conquer Cancer Foundation, International Association for the Study of Lung Cancer, National Cancer Institute (R01 CA205150), and the Damon Runyon Cancer Research Foundation.
免疫检查点阻断可改善部分非小细胞肺癌（NSCLC）患者的生存，但缺乏预测 PD-1 通路抑制剂反应的强大生物标志物。此外，我们对 NSCLC 肿瘤免疫微环境的多样性的理解仍然有限。
我们对 51 例 NSCLC 的肿瘤和免疫细胞进行了全面的流式细胞免疫分析，并将此分析与临床和组织病理学特征、下一代测序、mRNA 表达和 PD-L1 免疫组化（IHC）相结合。流式细胞仪分析确定了一个免疫“热”簇，其中富含表达高水平 PD-1 和 TIM-3 的 CD8 T 细胞，以及一个免疫“冷”簇，其中 CD8 T 细胞相对丰度较低，表达抑制性标志物。“热”簇高度富集与 T 细胞迁移和细胞毒性功能相关的基因表达，以及 IHC 高表达 PD-L1。免疫表型与 KRAS 或 EGFR 突变或患者吸烟史之间没有相关性，但我们确实观察到“热”簇中鳞状亚型和突变负荷较高的肿瘤富集。此外，约 20%的病例存在高 B 细胞浸润，其中一部分产生 IL-10。
我们的研究结果支持使用免疫相关指标来研究肺癌对免疫治疗的反应和耐药性。Robert A. 和 Renée E. Belfer 家庭基金会、Expect Miracles 基金会、Starr 癌症联盟、Stand Up to Cancer 基金会、Conquer Cancer 基金会、国际肺癌研究协会、美国国立卫生研究院（R01 CA205150）和 Damon Runyon 癌症研究基金会。
