Turning a Cold Tumor Hot: Targeting Tregs to Boost Immunotherapy in Prostate Cancer
A Columbia-led trial shows that reducing immune-suppressive T cells may improve outcomes in prostate cancer.
Prostate cancer treatment has not yet experienced the immunotherapy revolution seen in cancers such as melanoma and lung cancer. But new findings from a Columbia-led clinical trial suggest that carefully timed combination strategies may begin to change that paradigm.
Building on earlier discoveries that androgen deprivation therapy (ADT), a cornerstone of prostate cancer treatment, can activate the immune system, Columbia researchers launched an investigator-initiated clinical trial combining ADT with an immune checkpoint therapy designed to target immune suppression. The results, recently published Cell Reports Medicine, offer new insight into how prostate tumors might be made more responsive to immunotherapy and identify immune features that strongly predict patient outcomes.
A Brief Window of Opportunity
Prostate cancer is typically described as an “immune-cold” tumor, eliciting little immune activity and historically not responsive to immunotherapies. Prior work from Columbia investigators challenged that assumption, showing that ADT induces a short-lived immune response within the tumor microenvironment. Following hormone therapy, tumors temporarily show an influx of immune cells, particularly CD8+ T cells capable of killing cancer cells.
However, that immune activation is quickly counterbalanced. The same treatment also drives an increase in regulatory T cells, or Tregs—immune cells that suppress anti-tumor immune responses. Within weeks, these Tregs effectively “cool” the tumor again, closing the window for immunotherapy to work.
“That transient immune activation was the key observation,” said Aleksandar Z. Obradovic, MD, PhD, an oncology fellow at Columbia University Irving Medical Center and a lead author on the study. “The question became whether we could intervene during that window—and whether removing the brakes imposed by Tregs would improve outcomes.”
Targeting Immune Suppression
To test that idea, the research team designed a Phase I clinical trial combining ADT with an investigational CTLA-4 antibody. Unlike standard CTLA-4 inhibitors, this antibody was modified to not only block CTLA-4 but also enhance depletion of cells with high CTLA-4 expression, such as Tregs.
The single-center trial, launched at Columbia in 2020, enrolled 24 patients with high-risk primary prostate cancer. The primary goal was to assess safety, and investigators found the combination therapy to be well-tolerated, with no high-grade immune-related adverse events.
While the small cohort size and limited follow-up meant the study was not powered to detect differences in overall survival, the trial yielded a striking biological signal.
Tregs as a Predictor of Outcome
Using single-cell RNA sequencing, flow cytometry, and high-dimensional immune profiling, researchers analyzed tumor samples from three groups: untreated patients, patients treated with ADT alone, and patients receiving the ADT–CTLA-4 combination.
Consistent with earlier studies, ADT alone more than doubled the number of Tregs within tumors compared with untreated controls. Patients receiving the combination therapy had fewer Tregs than those receiving ADT alone, though not fewer than untreated patients. In other words, the therapy successfully prevented the ADT-induced surge in immune suppression, even if it did not fully eliminate Tregs.
Crucially, the degree of Treg depletion strongly correlated with clinical outcomes. Patients whose tumors showed lower Treg levels had significantly lower recurrence rates, even in this small cohort.
“That was the punch line,” Obradovic said. “Regardless of treatment arm, patients with fewer Tregs did better. That gives us strong justification for targeting these cells more effectively.”
Fluorescent images of prostate tumor tissue comparing ADT treatment alone (left) with ADT–CTLA-4 combination therapy (right)- showing that regulatory T cells (Tregs), marked by CD4 (green) and FOXP3 (pink), increase after ADT alone, but are reduced with combination therapy.
Understanding the Mechanism
The study also shed light on how the modified CTLA-4 antibody works in patients. The antibody’s engineered Fc region enhances binding to Fc-gamma receptors on macrophages, enabling these immune cells to recognize and eliminate Tregs through phagocytosis.
Advanced computational methods developed in the lab of Andrea Califano were critical to confirming this mechanism. Rather than relying solely on gene expression, which can be unreliable in single-cell data, the team inferred protein activity across immune signaling networks, allowing them to detect Fc-gamma receptor activity and link it directly to Treg depletion.
The analysis revealed that macrophage Fc-gamma receptor activity correlated with Treg depletion only in patients who received the CTLA-4 antibody, reinforcing the proposed mechanism of action. The study also found that higher levels of dendritic cells within tumors were associated with better outcomes, suggesting that the broader immune context may influence treatment response.
Next Steps: Toward More Effective Combinations
The research team is now planning follow-up trials using next-generation Treg-depleting CTLA-4 antibodies, with the goal of achieving more robust immune modulation and improved clinical benefit. In addition, the trial generated one of the most detailed molecular datasets to date on how ADT reshapes the immune landscape of high-risk primary prostate cancer, providing a valuable benchmark for future studies.
“This work moves the field beyond the question of whether hormone therapy has immune effects,” Obradovic said. “Now we understand which immune changes matter, how they influence outcomes, and how we might begin to manipulate them more effectively for new treatment strategies.”