MDK promotes M2 macrophage polarization to remodel the tumour microenvironment in clear cell renal cell carcinoma

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Clear cell renal cell carcinoma (ccRCC) immunotherapy efficacy is limited, particularly in advanced stages.
• Tumor microenvironment (TME) heterogeneity significantly impacts treatment response and presents a clinical challenge.
• Understanding immune regulation within the ccRCC TME is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To explore TME heterogeneity in ccRCC using multiomics data.
• To identify distinct ccRCC immune subtypes and develop a prognostic model.
• To elucidate the role of specific genes, like MDK, in ccRCC immunosuppression and treatment response.

Main Methods:

• Integrated analysis of publicly available ccRCC data, including single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (bulk RNA-seq), and somatic mutation data.
• Identification of ccRCC immune subtypes through combined scRNA-seq and bulk RNA-seq analysis.
• Validation of a prognostic model in The Cancer Genome Atlas (TCGA) and CheckMate cohorts.

Main Results:

• Three distinct ccRCC immune subtypes were identified, highlighting TME heterogeneity.
• A prognostic model based on immunosuppressive subtype cell signaling molecules was developed and validated.
• The gene MDK was identified as a critical regulator in the immunosuppressive subtype, associated with poor ccRCC prognosis and immunotherapy response.
• MDK was shown to promote M2 macrophage polarization via MDK-LRP1 interaction, and its inhibition suppressed this polarization.

Conclusions:

• The study reveals significant TME heterogeneity in ccRCC.
• A reliable prognostic model for ccRCC was established, identifying MDK as a key player in immunosuppression.
• Findings provide insights into MDK's role in the immunosuppressive TME, potentially guiding optimized ccRCC immunotherapy strategies.