A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma

被引：17

作者：

Pichler, Renate ^{[1
]}

Siska, Peter J. J. ^{[2
]}

Tymoszuk, Piotr ^{[3
]}

Martowicz, Agnieszka ^{[4
,5
]}

Untergasser, Gerold ^{[4
,5
]}

Mayr, Roman ^{[6
]}

Weber, Florian ^{[7
]}

Seeber, Andreas ^{[4
]}

Kocher, Florian ^{[4
]}

Barth, Dominik A. A. ^{[8
,9
]}

Pichler, Martin ^{[8
,9
]}

Thurnher, Martin ^{[10
]}

机构：

[1] Med Univ Innsbruck, Comprehens Canc Ctr Innsbruck, Dept Urol, Innsbruck, Austria

[2] Univ Hosp Regensburg, Dept Internal Med 3, Regensburg, Germany

[3] Data Analyt Serv Tirol, Innsbruck, Austria

[4] Med Univ Innsbruck, Comprehens Canc Ctr Innsbruck, Dept Internal Med Hematol & Oncol 5, Innsbruck, Austria

[5] Med Univ Innsbruck, Tyrolean Canc Res Inst TKFI, Innsbruck, Austria

[6] Univ Regensburg, Caritas St Josef Med Ctr, Dept Urol, Caritas St, Regensburg, Germany

[7] Univ Regensburg, Dept Pathol, Regensburg, Germany

[8] Med Univ Graz, Dept Internal Med, Div Oncol, Graz, Austria

[9] Med Univ Graz, Res Unit Noncoding RNAs & Genome Editing, Graz, Austria

[10] Med Univ Innsbruck, Dept Urol, Immunotherapy Unit, Innsbruck, Austria

来源：

FRONTIERS IN IMMUNOLOGY | 2023年 / 14卷

基金：

英国科研创新办公室;

关键词：

RCC; chemokines; immunotherapy; metabolism; OXPHOS; T cells; IDO; biomarker; CXCR3; MICROENVIRONMENT; IMMUNOTHERAPY; EXPRESSION; SIGNATURES; INSIGHTS; MODELS; TISSUE; CCR3;

D O I：

10.3389/fimmu.2023.1095195

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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. Chemokine(high) 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.

引用

页数：20