Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Pichler, R; Siska, PJ; Tymoszuk, P; Martowicz, A; Untergasser, G; Mayr, R; Weber, F; Seeber, A; Kocher, F; Barth, DA; Pichler, M; Thurnher, M.
A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma.
Front Immunol. 2023; 14: 1095195
Doi: 10.3389/fimmu.2023.1095195
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- Co-Autor*innen der Med Uni Graz
- Barth Dominik Andreas
- Pichler Martin
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Carcinoma, Renal Cell - administration & dosage
- CD8-Positive T-Lymphocytes - administration & dosage
- T-Cell Exhaustion - administration & dosage
- Chemokines - genetics
- Chemokine CXCL9 - genetics
- Kidney Neoplasms - administration & dosage
- Tumor Microenvironment - administration & dosage
- Find related publications in this database (Keywords)
- RCC
- chemokines
- immunotherapy
- metabolism
- OXPHOS
- T cells
- IDO
- biomarker