Characterization of the immunosuppressive tumour microenvironment in a mouse model of clear cell renal cell carcinoma

Abstract: Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer with a high mortality rate. The prognosis of metastatic ccRCC is poor, and until recently 5-year survival rates were only approximately 10%. ccRCC tumours are typically highly immune-infiltrated tumours and the clinical introduction of immune checkpoint inhibitors (ICIs) has greatly improved current therapy. Currently, combination therapy of ICIs with other inhibitors, such as tyrosine kinase inhibitors (TKIs), has increased 5-year survival rates of patients with advanced ccRCC to
approximately 40%. However, not all patients benefit from ICI treatments, and due to a lack of knowledge about the tumour microenvironment in ccRCC, there are no biomarkers to predict the effectiveness of treatment in each patient. Previous research has revealed that there is an elevated myeloid and T cell infiltration in ccRCC tumours. In our VpR mouse model (Ksp-CreERT2; VhlΔ/Δ; Trp53Δ/Δ; Rb1Δ/Δ), ICI treatments with either α-PD-1 and α-CTLA-4 or a combination of other inhibitors showed no therapeutic effect. scRNA-seq of VpR tumours indicated there was no upregulation of PD-1 and CTLA-4 ligands. Instead, myeloid cells
express genes that are related to T cell suppression. CCL5, CXCL2, CXCL10, and MIF were found in conditioned medium (CM) from VpR mouse tumour cell lines and induced the migration of macrophages. Moreover, CM led to mis-differentiation toward monocytic myeloid-derived suppressor cells (M-MDSCs) and tumour-associated macrophage 2 (TAM2). These differentiated BMCs not only inhibited CD8+ T cell proliferation but also stimulated CD8+ T cells to express exhausted signatures. Finally, CXCR2 and MIF receptors showed a role in regulating myeloid cell differentiation and macrophage migration. In conclusion, we demonstrate that ccRCC tumour could suppress immune responses by inducing recruitment and
mis-differentiation of myeloid cells in the VpR mouse model and reveal that ICI resistance might be overcome by blocking multiple checkpoint receptors.
Previous studies have shown elevated CARMA3 (CARD10) in various solid tumours and it plays key roles in multiple cellular responses, including cell migration, invasion, and poor prognosis in RCC. It’s known that the CARMA3-MALT1-BCL10 (CBM) complex activates NF-κB and MAPK pathways through GPCRs and EGFR. However, the individual mediators and mechanisms that control CARMA3 activation in the CBM complex and, subsequently, its
immunomodulatory functions remain unclear. In an immunoprecipitation screen for interactors of pVHL we identified CARMA3. RNA-seq revealed that NF-κB, HIF-α and metabolic signaling pathways are downregulated upon CARMA3 mutation in ccRCC cell lines. Migration of CARMA3-mutated cells was decreased in 786-O not in RPTEC cells. Together, these findings provide preliminary evidence to suggest that VHL may be involved in the CARMA3 signaling pathway in ccRCC

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2023

Classification and Topics

• Classification: Biowissenschaften, Biologie
• Keyword: Tiermodell ; Krebs ; Tumorwachstum ; Zelldifferenzierung ; Immuntherapie

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2023
• Creator: Huang, Hsin
• Contributor: Frew, Ian ; Brummer, Tilman ; Pahl, Heike L. ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie ; Zentrum Translationale Zellforschung

Further information

• DOI: 10.6094/UNIFR/240268
• URN: urn:nbn:de:bsz:25-freidok-2402683
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:25 AM CEST