Sex hormones limit cancer immunotherapy success

Scientists have discovered how the sex hormone androgen, most commonly testosterone in men, can limit the body’s response to cancer immunotherapy, a finding that may help make those therapies more consistently effective. The research also sheds new light on what causes the immune system to function differently in men compared to women.

“We have all sorts of really intriguing questions to ask now that we have demonstrated a very direct effect of androgens on limiting killer T cells and their potential to kill cancer cells,” said Amy Moran, Ph.D., who led the research. Moran is an assistant professor of cell, developmental and cancer biology in the OHSU School of Medicine.

Image: T cells (red) attack a cancer cell in this electron microscope view by Rita Elena Serda (NCI Visuals Online).The researchers were driven to find out why some men with life-threatening prostate cancer benefitted from immunotherapy drugs called checkpoint inhibitors and achieved lasting suppression of tumor growth, while others in the same clinical trial were not helped. (The clinical trial was the first to show meaningful clinical activity for immune checkpoint inhibitors in men with aggressive, advanced-stage prostate cancer.)

“What was unique among those who benefitted was lower levels of activity of the receptor that binds testosterone, the androgen receptor, in killer T cells in their tumors,” Moran said. She and her team published the research in Nature.

The immune checkpoint inhibitors work by unleashing the immune system’s cancer-fighting killer T cells. In a series of experiments, Moran and colleagues found that T cells within tumors and healthy tissue express androgen receptors and that exposure to androgen hormones effectively disables the T cells.

When the researchers blocked androgen signaling in laboratory mice with tumors, it made the cancers vulnerable to immune checkpoint inhibitors. And the researchers showed that it did so by directly enhancing T cell function.

“If you strip the androgen away, you can make the T cells work again,” Moran said.

Amy Moran, Ph.D. (center) with co-authors Zheng Xia, Ph.D., (left) and Julie Graff, M.D.

Digging deeper, the researchers found that blocking androgen receptor activity in T cells prevented T cell exhaustion and improved responsiveness to checkpoint inhibitor treatment by way of increased expression of interferon gamma, a signaling molecule that is required for sparking the immune system to fight cancer.

The findings support the idea of using androgen-blocking drugs to make immunotherapies work more consistently against prostate cancer, and perhaps other kinds of cancer as well. “We would love to open clinical trials enrolling solid tumor patients who are not responding to their cancer immunotherapy to find out if blocking androgen receptor activity can improve the response,” Moran said.

She said that measuring androgen activity in T cells could prove useful as a way to identifying cancer patients likely to benefit from checkpoint inhibitors because of reduced androgen activity. “We’re trying to develop an assay where we could stain patient biopsies and measure androgen activity prior to therapy,” Moran said.

Beyond cancer immunotherapy, Moran said the research could help explain female-male differences in immune response, such as why women are more protected from infectious diseases, and why men are more protected from auto-immune diseases. Androgens, including testosterone, that can directly suppress immune T cells are more abundant in male bodies.

In the future, it may be possible to target androgen signaling to boost immune responses to vaccination, or to throttle back immunity in people with auto-immune diseases.

Further reading:

Androgen receptor activity in T cells limits checkpoint blockade efficacy by Xiangnan Guan, Fanny Polesso, Chaojie Wang, Archana Sehrawat, Reed M. Hawkins, Susan E. Murray, George V. Thomas, Breanna Caruso, Reid F. Thompson, Mary A. Wood, Christina Hipfinger, Scott A. Hammond, Julie N. Graff, Zheng Xia and Amy E. Moran. Nature (March 23, 2022)

Advancing immunotherapy for life-threatening prostate cancer by Joe Rojas-Burke. Cancer Translated (Feb. 19, 2020)

 

The research was funded in part by the Collins Medical Trust, OHSU Foundation, Prostate Cancer Foundation, Murdock Natural Sciences, and a sponsored research agreement with MedImmune.

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