Primary Prostate Cancer Establishes a Suppressive Immune Microenvironment
Key findings
- In this study, high-resolution, single-cell RNA sequencing was used to characterize changes in tumor, immune and non-immune stromal cells within the prostate tumor microenvironment
- The findings were complemented by spatial transcriptomic analysis and a novel computational method for context-specific analysis of the transcriptional impact of tumor cells on neighboring stromal cells
- Key observations were that primary prostate cancer establishes a suppressive immune microenvironment and the tumor microenvironment exhibits a high angiogenic gene expression pattern
- Tumor-induced alterations of neighboring cells were found to promote tumorigenesis and progression
- The findings speak to how prostate tumors avoid the immune system and set up a tumor permissive niche on the road to progression and metastasis; this combined dataset will help the field identify areas of vulnerability amenable to therapeutic intervention
Localized prostate cancer has been extensively studied with bulk transcriptomic and genomic sequencing approaches, which provided insights into oncogenic drivers and recurrent molecular changes.
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Now, researchers at Massachusetts General Hospital have become the first to rigorously characterize immune cells within the prostate microenvironment at the single-cell level. In Nature Communications, they describe a highly immune suppressive tumor microenvironment (TME) that exhibits high stromal angiogenic activity, among other findings that should aid in developing new therapies.
The work was conducted by a multidisciplinary team, including Taghreed Hirz, PhD, and Shenglin Mei, PhD, research fellows in the Center for Regenerative Medicine at Mass General, David B. Sykes, MD, PhD, hematologist and principal investigator in the Center, Philip J. Saylor, MD, a physician investigator at the Mass General Cancer Center, and colleagues.
Methods
The research team collected fresh prostate tissue samples from 19 treatment-naive patients who underwent radical prostatectomy. In 15 of those, matched benign prostate tissue adjacent to the tumor was also sampled. Control prostate tissue was collected from four patients who underwent cystoprostatectomy for bladder cancer and one rapid autopsy of a patient who died of metastatic non-small cell lung cancer.
The prostate TME typically contains few immune cells. The team processed the tissues using a dissociation protocol that enriched and preserved immune cells, then examined the immune microenvironment at high resolution via single-cell RNA sequencing.
To validate their single-cell findings, the researchers used a highly detailed spatial transcriptomic technique (Slide-seqV2) where the tissue architecture and cell–cell proximity relationships were preserved. They developed a new computational method to examine the transcriptional impact of tumor cells on neighboring stromal cells.
Key Observations
The principal findings were:
Epithelial cells—Detection of genomic aberrations distinguished normal and malignant epithelial cells, and by deriving a succinct prostate tumor gene signature, it was possible to identify tumor samples across four independent datasets.
Angiogenic activity—Endothelial cells were involved in sprouting angiogenesis and vascular endothelial growth factor pathways, as well as upregulation of cell migration and proliferation pathways relevant to prostate cancer progression.
Immune microenvironment—Tumor-inflammatory monocytes scored highest for accumulation of myeloid-derived suppressor cells, and that gene signature was significantly higher in tumor cells than healthy tissue, suggesting a role for tumor-inflammatory monocytes in prostate tumor growth through immunosuppressive activity.
Lymphoid compartment—Cytotoxic T cells and natural killer cells showed high exhaustion signatures in the tumor fraction; there were no significant differences in T cells between low-grade and high-grade cases, suggesting even low-grade tumors had already established a highly immunosuppressive microenvironment.
Therapeutic Implications
It's hoped that this combined dataset of single-cell and spatial transcriptomic analysis will prove broadly useful for the field. Biological validation of relationships between tumors and adjacent immune and stromal cells will lead to better understanding of prostate cancer progression and should identify new therapeutic targets.
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