Potential Strategy Identified for Treating Bone-Metastatic Clear Cell RCC

Within normal bone marrow, macrophages, and cytotoxic T cells form an important initial line of defense against disseminating cancer cells. However, the arrival of cancer cells can lead to an immunosuppressive tumor microenvironment that disrupts T cell-mediated cell killing, favoring tumor cell expansion.

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Clear cell renal cell carcinoma (ccRCC) is among the cancers that have a predilection to metastasize to bone. Researchers at Massachusetts General Hospital and colleagues used single-cell RNA sequencing to define what cells, molecules, and cell states make up the tumor microenvironment in bone-metastatic human ccRCC, with the goal of identifying therapeutic targets.

Shenglin Mei, PhD, an instructor in the Center for Regenerative Medicine at Mass General, Ninib Baryawno, PhD, Adele Alchahin, MSc, and Ioanna Tsea, BSc, of the Karolinska Institutet in Sweden, and colleagues report the findings in Genome Medicine.

Methods

The participants in the study were nine patients undergoing treatment of spinal cord compression related to metastatic ccRCC. The researchers collected bone-metastatic tumor samples (n=9), liquid bone marrow at the vertebral level of spinal cord compression (n=4), and liquid bone marrow from a vertebral body distant from the tumor site (n=4).

For comparison the team collected nine benign bone marrow samples from patients undergoing hip replacement surgery, 12 samples of healthy bone marrow, 14 ccRCC primary tumors, and nine matched adjacent normal samples.

Key Findings

The principal results were:

• The bone marrow of patients with bone-metastatic ccRCC was immunosuppressive, featuring increases in exhausted CD8+ cytotoxic T cells, T regulatory cells, and tumor-associated macrophages with distinct transcriptional states
• A TREM2+SPP1+ subset of tumor-associated macrophages was notably enriched in bone metastatic lesions and was associated with worse patient survival
• Metastatic tumor samples demonstrated mesenchymal stromal cells that were transcriptionally similar to cancer-associated fibroblasts (CAFs), appeared to support the epithelial-to-mesenchymal transition in tumor cells and were associated with poor progression-free and overall survival
• The same stromal cell subpopulation in bone-metastatic ccRCC was associated with an increase in the RANK–RANKL axis pathway, which promotes bone resorption, and a decreased level of osteoprotegerin, which promotes bone growth and homeostasis

Commentary

One-third of patients with advanced ccRCC have bone metastasis at the time of presentation, and the five-year survival rate is only 12%. Novel therapies that target diverse cellular constituents of the tumor microenvironment are a critical need.

The mesenchymal stromal cells detected in ccRCC bone metastases may be similar to the CAFs seen in other cancers. CAFs are a key component of the tumor microenvironment; they can regulate cancer proliferation and metastasis by remodeling the extracellular matrix and producing growth factors, and they can influence angiogenesis and immune response.

Intriguingly, bone metastatic samples in this study showed expression of interleukin-6, interleukin-8, vascular endothelial growth factor A, and transforming growth factor β-1. Targeting mesenchymal stromal cells in ccRCC bone metastases may prove to be an effective therapeutic strategy.

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