T cell attacking cancer cell, illustration

New research shows that targeting the activin receptor 1C on T cells may boost immune system attack against cancer cells. As a potential new anticancer immunotherapy, it opens the door to new treatment protocols aimed at blocking its function.

The team first found that the levels of protein activins, including A and B, are elevated in tumor-bearing mice and cancer patients. They observed that these proteins promote differentiation of CD4+ T helper cells to transform into regulatory T-cells (Tregs), which suppress immune system activity. However, blocking activin receptor 1C on CD4+ T cells helps prevent the accumulation of immune-suppressing Tregs in tumors and slows tumor growth. Their research is published in OncoImmunology.

“We found that adding activin A or B was able to increase the percentage of positive Tregs,” says first author Ying Zheng, of the laboratory of Drew Pardoll, director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.

Further study revealed that activin receptor 1c was uniquely expressed on Tregs. To learn more about the role of this receptor, the investigators used knock-out activin receptor 1C mice and observed that these mice showed significantly reduced tumor growth.

In their next experiments in mice, the researchers generated a monoclonal antibody targeting activin receptor 1C and observed that it reduced melanoma tumors. The effects were even more pronounced when that antibody was combined with an anti-PD-1 antibody —including in tumors that otherwise do not usually respond to anti-PD-1 blockade. “These observations strongly indicate that activins’ impact on T cells is relevant in the tumor microenvironment, promoting immunosuppression,” according to the authors.

The team explains that one possible mechanism for this additive effect is that activin-receptor 1C signaling operates through a distinct pathway from the PD-1 ligand receptor. “Based on our understanding, anti-activin receptor 1C antibodies target CD4+ regulatory T cells and anti-PD-1 antibodies directly unleash suppressed cytotoxic CD8+ T cells,” the authors write. “Although both antibody treatments ultimately enhance the functionality of CD8+ T cells in eradicating cancer cells, it is important to emphasize that these antibodies exert their effects on distinct immune cell populations, additively contributing to their common objective.” These observations strongly indicate that activins’ impact on T cells is relevant in the tumor microenvironment, promoting immunosuppression.

“We have identified a new target for anticancer immunotherapy,” says Pardoll. “Our discovery could lead to an entirely new class of immunotherapies that may enhance the effects of existing cancer therapies and further personalize cancer care.”

Because the human activin receptor 1C is almost identical to the mouse activin receptor 1C, the research team is hopeful that similar efficacy will be achieved in humans. The similarity will also help expedite preclinical studies testing anti-activin receptor 1C antibody therapy candidates.

The team is currently collaborating with partners to develop several potential candidate antibodies with the goal of initiating clinical studies in 2025.

“Blocking activin receptor 1C-signaling is a promising and disease-specific strategy to impede the accumulation of immunosuppressive Tregs in cancer,” the authors write. They further suggest that blood tests can identify patients with high levels of activin who may be more likely to benefit from anti-activin receptor 1C antibody therapies, possibly allowing more precise identification of patients likely to benefit from the therapy.

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