Genetic Signature Predicts Metastasis, Survival in Clear Cell Renal Cell Carcinoma

Resistance to checkpoint inhibitor immunotherapy is common in patients with clear cell renal cell carcinoma (ccRCC). Checkpoint blockade targets T cells within the tumor microenvironment, but the microenvironment may have other tumor-protective capabilities.

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Researchers at Massachusetts General Hospital are working toward improving therapies for metastatic RCC by deepening the understanding of how tumor cells interact with their microenvironment. They found that simultaneous expression of four specific genes predicts survival and metastasis in human ccRCC, and identified other potential therapeutic targets in Nature Communications.

This work highlights the importance of a coordinated and dedicated multidisciplinary team. The authors include Shenglin Mei, PhD, a research fellow in the Department of Medicine at Mass General, Philip J. Saylor, MD, a physician investigator at the Mass General Cancer Center, David B. Sykes, MD, PhD, hematologist and principal investigator in the Center for Regenerative Medicine, Douglas Dahl, MD, surgeon and chief of the Division of Urologic Oncology, and their colleagues.*

Methods

The researchers used coordinated surgical and research teams to bring samples of freshly resected primary ccRCC tumors from the operating room to the laboratory. Single-cell RNA sequencing was performed on tumor tissue and adjacent normal tissue from nine treatment-naïve patients, including two who had metastases at multiple sites at the time of diagnosis. 157,881 tumor cells and 35,827 normal cells were analyzed.

A Distinct Metastatic Tumor Cell Cluster

Intratumor heterogeneity has been widely reported in ccRCC and was confirmed in this study. The researchers analyzed variation among different individuals in the number of copies of specific segments of DNA and determined different patients shared four major tumor clusters:

• Clusters 1 and 2, found mainly in patients who had nonmetastatic RCC, were defined by loss of chromosome 3p, driven by genes associated with catabolic and metabolic processes
• Cluster 3, characterized by losses on chromosomes 3p, 6p, and 14, was associated with high expression of APOE, APOC1, ACSM2A, and ACSM2B
• Cluster 4 had the most abundant copy number aberrations, was notably more common in patients with multiple metastatic sites, and was characterized by upregulation of SAA1, SAA2, and APOL1 (genes known to be upregulated in high-grade ccRCC), and MET (a tyrosine kinase receptor involved in tumor cell proliferation, survival and migration that is one of the therapeutic targets of cabozantinib)

Cluster 4 was significantly associated with poor survival when the team evaluated data on two independent RCC cohorts. That gene signature was also detected in tumor cells in bone metastasis sites in seven additional patients with RCC. Future research on this cluster may highlight targets for the prevention or treatment of RCC metastasis.

Other Potential Therapeutic Targets

RCC often evades immune recognition even though renal tumors are highly infiltrated with immune cells. By examining the immunosuppressive environment and stromal alterations in the treatment-naïve patients, the researchers identified several potential therapeutic targets:

The CD70–CD27 axis—Both CD70 ligand and its receptor, CD27, were found to be in close proximity within the spatial context of the tumor. CD70 was produced by tumor cells and CD27 was upregulated in immunosuppressive T cells, including CTL-1, Tregs. CD70–CD27 signaling was higher in tumor tissue than in adjacent tissue and correlated with T cell exhaustion. CD70 may have immunosuppressive effects, and CD27 merits exploration as a therapeutic target in ccRCC.

The CXCL10–CXCR3 axis—Myeloid cells expressing CXCL9 or CXCL10 were found to interact with CXCR3-expressing T cells. CXCL9/10 signaling via CXCR3 might promote tumor progression by deregulating inflammatory pathways.

It's hoped that the findings from this study will prompt further preclinical studies that facilitate the development of additional therapies for patients suffering from ccRCC.

*Other Mass General colleagues who contributed to this study include John Shin, MD, director of Spinal Deformity and Spine Oncology Surgery in the Department of Neurosurgery, Chin-Lee Wu, MD, PhD, director of Genitourinary Pathology Services, and David T. Scadden, MD, director of the Center for Regenerative Medicine.

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