Researchers Identify Immune Cells That Contribute to Prostate Cancer Resistance and Explore Ways to Counteract Them

Scientists have uncovered a specific subset of immune cells that may unintentionally aid prostate cancer progression and resistance to treatment. The study, published in Molecular Cancer Research, focused on tumor-associated macrophages—immune cells typically responsible for clearing dead cells and combating infections. However, in advanced prostate cancer, especially within the bone where the disease often becomes most aggressive, some macrophages are reprogrammed by tumor cells to suppress the body's immune response and facilitate tumor growth and metastasis.

Led by Assistant Professor Shenglin Mei from Virginia Tech's Fralin Biomedical Research Institute, the research utilized advanced techniques such as single-cell RNA sequencing, spatial transcriptomics, and digital spatial profiling to map immune cell activity within tumors. The team identified four macrophage subtypes, with one characterized by the proteins SPP1 and TREM2, predominantly located inside tumor regions. These cells were associated with increased blood vessel formation, immune suppression, and cancer spread.

Using spatial analysis, researchers observed that most inflammatory macrophages—potentially tumor-fighting—were located outside tumor boundaries. Conversely, the subtype producing SPP1 and TREM2 was found within the tumor core, directly interacting with cancer cells. "While macrophages can aid in combating cancer, certain subtypes foster an immunosuppressive environment that shields tumors from immune attacks," Mei explained.

Further experiments in mice demonstrated that blocking the SPP1 protein made tumors more susceptible to immunotherapy. Combining this approach with immune checkpoint inhibitors significantly enhanced immune responses and slowed tumor growth. This suggests that targeting macrophages expressing SPP1 and TREM2 could restore immune activity and improve treatment outcomes, especially in prostate cancer resistant to conventional immunotherapy.

Prostate cancer remains the second most diagnosed cancer among men worldwide, with over 1.47 million new cases in 2022. Understanding the tumor microenvironment—the surrounding immune cells, blood vessels, and signaling molecules—has been crucial in unveiling mechanisms of immune escape.

This research integrated multiple cutting-edge methods and analyzed extensive datasets from diverse sources, confirming the relevance of these findings in both human samples and animal models across different disease stages. The collaboration involved institutions such as Virginia Tech, Harvard Medical School, Massachusetts General Hospital, the University of Chicago, and the Karolinska Institute in Sweden. Many co-authors are clinician-scientists contributing clinical insights and patient samples.

Funding was provided by the Prostate Cancer Foundation, the National Institutes of Health, and support from the Red Gates Foundation. Building upon Mei's earlier work on tumor microenvironments in prostate cancer, this study offers new insights into how immune cells are manipulated during disease progression and how they can be targeted for novel therapies.

"This approach exemplifies the future of precision medicine, combining genomics, spatial profiling, and immune analysis to identify actionable targets in prostate cancer," Mei stated. The findings mark a significant step toward overcoming treatment resistance and improving outcomes for patients with advanced prostate cancer.