Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response
Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response
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DOI：
10.1111/cei.13567
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发表时间：
2021-02-09
影响因子：
4.6
通讯作者：
Manley, B.
中科院分区：
文献类型：
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作者：
Hajiran, A.;Chakiryan, N.;Manley, B.
更清楚地了解转移性透明细胞肾细胞癌（ccRCC）中的肿瘤免疫微环境（TIME）可能有助于制定精确的治疗策略。我们试图在ccRCC中识别具有临床意义的TIME特征。我们使用定量多重免疫荧光和相关免疫标记物组研究了39例转移性ccRCC患者的肿瘤。在三个感兴趣区域（ROI）中分析细胞密度：肿瘤核心、肿瘤-间质界面和间质。以中位数为阈值，将患者分为低和高标记物密度组。在控制临床变量的同时，使用对数秩和考克斯回归分析来比较生存结局与免疫细胞分布模式。在原发性和转移性肿瘤的多个ROI中，巨噬细胞（CD 68（+）CD 163（+）CD 206（+））密度增加与预后不良显著相关。在原发性肿瘤中，T-bet（+）1型辅助性T细胞（Th 1）密度在肿瘤-间质界面最高（P = 0，中心点0021），CD 3和T-bet共表达增加与总生存率（P = 0，中心点015）和免疫治疗后生存率（P = 0，中心点014）的改善相关。在转移性肿瘤样本中，减少的叉头盒蛋白3（FoxP 3）（+）T调节细胞密度与免疫治疗后的存活率改善相关（P = 0，中心点016）。TIME内巨噬细胞标志物增加和Th 1 T细胞标志物减少与总体生存率和治疗结局较差相关。免疫标记物如FoxP 3在整个时间内表现出一致的水平，而其他标记物如T-bet在不同的ROI中表现出显著的差异。这些发现表明，肿瘤核心外的TIME分析可以确定转移性ccRCC患者的临床相关性。
A clearer understanding of the tumor immune microenvironment (TIME) in metastatic clear cell renal cell carcinoma (ccRCC) may help to inform precision treatment strategies. We sought to identify clinically meaningful TIME signatures in ccRCC. We studied tumors from 39 patients with metastatic ccRCC using quantitative multiplexed immunofluorescence and relevant immune marker panels. Cell densities were analyzed in three regions of interest (ROIs): tumor core, tumor-stroma interface and stroma. Patients were stratified into low- and high-marker density groups using median values as thresholds. Log-rank and Cox regression analyses while controlling for clinical variables were used to compare survival outcomes to patterns of immune cell distributions. There were significant associations with increased macrophage (CD68(+)CD163(+)CD206(+)) density and poor outcomes across multiple ROIs in primary and metastatic tumors. In primary tumors, T-bet(+) T helper type 1 (Th1) cell density was highest at the tumor-stromal interface (P = 0 center dot 0021), and increased co-expression of CD3 and T-bet was associated with improved overall survival (P = 0 center dot 015) and survival after immunotherapy (P = 0 center dot 014). In metastatic tumor samples, decreased forkhead box protein 3 (FoxP3)(+) T regulatory cell density correlated with improved survival after immunotherapy (P = 0 center dot 016). Increased macrophage markers and decreased Th1 T cell markers within the TIME correlated with poor overall survival and treatment outcomes. Immune markers such as FoxP3 showed consistent levels across the TIME, whereas others, such as T-bet, demonstrated significant variance across the distinct ROIs. These findings suggest that TIME profiling outside the tumor core may identify clinically relevant associations for patients with metastatic ccRCC.