肾细胞癌（RCC）经常被免疫细胞浸润，这一过程受趋化因子的调控。RCC肿瘤微环境（TME）中的CD8+T细胞可能会疲劳，这很可能影响治疗反应和生存率。本研究的目的是评估趋化因子驱动的T细胞招募、RCC TME中T细胞疲劳以及导致其功能失调的代谢过程。分析了8个公开可用的RCC转录组数据集（n=1819）和一个单细胞RNA测序数据集（n=12）。采用免疫去卷积、半监督聚类、基因集变异分析和基于蒙特卡罗的代谢反应活性模拟。在28个可用的趋化因子基因中，CXCL9/10/11/CXCR3、CXCL13/CXCR5和XCL1/XCR1 mRNA表达在RCC中显著增加，与所有调查的集合中的肿瘤浸润效应器记忆和中心记忆CD8+T细胞也强烈相关。M1 TAM、T细胞、NK细胞以及肿瘤细胞被确定为这些趋化因子的主要来源，而T细胞、B细胞和树突状细胞则主要表达对应的受体。高趋化因子表达和高CD8+T细胞浸润的RCC特征集群显示出IFN/JAK/STAT信号的强烈激活，并表达了多个T细胞耗竭相关转录本。趋化因子高的RCC具有代谢重编程的特征，特别是下调的OXPHOS和增加的IDO1介导的色氨酸降解。没有任何检查的趋化因子基因与生存或免疫治疗反应显著相关。我们提出了一种介导CD8+T细胞招募的趋化因子网络，并确定了T细胞疲劳、改变的能量代谢和高IDO1活性是它们抑制的关键机制。同时靶向耗竭途径和代谢可能是RCC治疗的有效途径。 版权所有 © 2023 Pichler，Siska，Tymoszuk，Martowicz，Untergasser，Mayr，Weber，Seeber，Kocher，Barth，Pichler和Thurnher。

Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.Copyright © 2023 Pichler, Siska, Tymoszuk, Martowicz, Untergasser, Mayr, Weber, Seeber, Kocher, Barth, Pichler and Thurnher.