School of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
J Immunother Cancer. 2023 Aug;11(8). doi: 10.1136/jitc-2023-007240.
The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized.
We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases.
We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation.
Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.
肿瘤微环境（TME）有助于癌症的进展和对治疗的反应，包括肾细胞癌（RCC）。先前的分析研究，包括单细胞转录组学，通常涉及有限的样本量且缺乏空间方向。RCC 脑转移的 TME，这是发病率的主要原因之一，也在很大程度上尚未得到描述。
我们在 NanoString GeoMx 平台上使用 52 种经过验证的免疫肿瘤标志物进行数字空间分析，这些标志物代表 RCC 组织微阵列中 RCC 的进展阶段，包括脑转移。我们对 76 个原发性肿瘤、27 个相邻的组织学正常的肾脏样本和 86 个转移灶进行了分析，其中包括 24 个脑转移灶。
我们在两个独立的队列中观察到，与原发性肿瘤相比，转移灶中的免疫检查点（TIM-3 和 CTLA-4）、细胞毒性（GZMA 和 GZMB）和 T 细胞激活（CD25）蛋白表达较低。我们还发现转移灶中的巨噬细胞发生了变化，在易发生脑转移的患者中，转移性样本中的 M1 样炎症巨噬细胞标志物（HLA-DR 和 CD127）表达较少。与颅外转移相比，脑转移灶中发现抗凋亡 BCL-2 家族蛋白 BCL-XL 表达较高，固有免疫激活剂 STING 表达较低。脑转移灶中 TME 中 TIM-3 和 CD40 的表达较低似乎与生存时间延长有关，这一发现需要进一步验证。
与原发性肿瘤相比，包括脑转移在内的 RCC 转移瘤表达的多种免疫激活标志物和当前或研究性治疗靶点的水平较低。我们的研究结果可能对设计未来的生物标志物和治疗研究具有重要意义，并可能有助于开发针对脑转移的特异性治疗方法。
