Blocking key immune cells could make prostate cancer treatable

Scientists have revealed how certain immune cells may be quietly helping prostate cancer grow - and how blocking them could help the body fight back.

The study, published July 2 as the cover story in Molecular Cancer Research, identifies a group of cells called macrophages that, instead of protecting the body, appear to shield tumors from attack and promote tumor metastasis. 

These cells are typically the immune system's housekeeping crew - engulfing dead cells and responding to infection - but in prostate cancer, some are reprogrammed by tumors to suppress the body's immune responses and promote their own spread.

Led by Assistant Professor Shenglin Mei of the Fralin Biomedical Research Institute Cancer Research Center in Washington, D.C., the study focused on tumor-associated macrophages, in advanced prostate cancer - particularly in the bone, where the disease is most deadly and difficult to treat.

Among four macrophage subtypes identified, one stood out: a group marked by the proteins SPP1 and TREM2. These cells were found clustered inside tumor regions - not in surrounding tissue - and were linked to blood vessel growth, impaired immune activity, and the spread of cancer in the body. 

Using spatial analysis - a technique that maps where cells are located within a tumor - researchers found that inflammatory, potentially tumor-fighting macrophages tended to remain outside tumor boundaries, but a specific subtype that produces the troublesome SPP1 and TREM2 proteins was found deep inside the tumors, in close contact with cancer cells. 

Macrophages often aid in fighting cancers. However, certain subtypes foster an immune-suppressive environment, hindering the body's natural defenses."

Shenglin Mei, Assistant Professor, Fralin Biomedical Research Institute Cancer Research Center 

In follow-up experiments, Mei and his colleagues tested whether blocking these cells could improve treatment. In mice with prostate tumors, they used an antibody to block the SPP1 protein - and found that tumors were more vulnerable to immunotherapy.

While immune checkpoint inhibitors have worked in many other cancers, they've failed in prostate cancer. But in this study, combining anti-SPP1 treatment with immunotherapy significantly boosted the immune response.

"Targeting SPP1/TREM2 tumor associated macrophages reversed immunosuppression, allowing more T cells - the immune system's primary defenders - to infiltrate the tumor, resulting in slowed cancer progression," Mei said.

Prostate cancer is the second most commonly diagnosed cancer in men in the United States and globally, with an estimated 1.47 million new cases worldwide in 2022, according to the World Cancer Research Fund. 

Scientists have long suspected that the tumor microenvironment - the mix of immune cells, blood vessels, and signaling molecules around a tumor - plays a role in helping cancer escape detection. But this new study reveals, in greater detail, which cells are involved and how they're working.

To make this discovery, Mei's lab combined advanced techniques - including single-cell RNA sequencing, spatial transcriptomics, and NanoString digital spatial profiling - to map immune cell activity and location. 

They also analyzed large-scale, publicly available datasets from hundreds of prostate cancer patients, ensuring their findings held up across human samples, mouse models, and disease stages.

"This is about more than just one cell type," said Mei, who also has an appointment with the Department of Biomedical Sciences and Pathobiology in the Virginia-Maryland College of Veterinary Medicine. "It's about using spatial and single-cell analysis together to uncover vulnerabilities that we couldn't see before."

The research is the product of a multi-institutional collaboration that included Virginia Tech, Harvard Medical School, Massachusetts General Hospital, the University of Chicago, and Sweden's Karolinska Institute. 

Many of the co-authors are physician-scientists who provided access to patient samples and clinical insights, Mei said. The project was supported by the Prostate Cancer Foundation, which awarded Mei a Young Investigator Award, and by the National Institutes of Health. Mei is among a cohort of new cancer research faculty at the research institute whose recruitment was supported by the Red Gates Foundation.

This work builds directly on Mei's earlier studies - a 2021 Cancer Cell paper that revealed an immunosuppressive tumor microenvironment in bone metastases, and a 2023 Nature Communications study that mapped immune cell patterns in primary tumors. 

The new study expands on that foundation, integrating old and new datasets to reveal a previously hidden player in prostate cancer progression.

"This is exactly the kind of innovative and collaborative precision medicine research that we hope to foster with this new center," said Chris Hourigan, director of the Fralin Biomedical Research Institute Cancer Research Center in Washington, D.C. "Integrating cancer genomics and computational oncology expertise may lead not only to new biological understanding but also, we hope, to potentially actionable solutions for the problem of cancers."