Study identifies CXCL11 as driver of endocrine resistance in some breast cancers

Up to 20% of hormone receptor-positive breast cancers don’t respond to antiestrogen therapies, and a study published in The Journal of Clinical Investigation suggests that CXCL11, a protein secreted by immune cells within these tumors, causes them to grow even in the absence of estrogen. The study said these findings point to new therapeutic strategies to overcome resistance and improve outcomes for patients. Researchers also said ED-resistant tumors appear to have significantly more T cells and may be more responsive to immunotherapies.

Nearly 80% of breast cancers are hormone receptor-positive and thus rely on estrogen to multiply and survive. Treatment of these cancers is typically based on depriving them of estrogen through various means, such as drugs that inhibit estrogen production. Although these therapies have significantly increased breast cancer survival, a subset of hormone receptor-positive cancers don’t respond, often leading them to recur after other treatments, including surgery and radiation.

To examine why these cancers resist antiestrogen therapies, researchers looked at 173 tumor samples from Vanderbilt University Medical Center, UT Southwestern, and Parkland Health. They compared those that responded to estrogen-depriving treatment with those that had become resistant. The researchers found a significant increase in gene expression for various immune pathways in the resistant tumors, suggesting the presence of immune cells within the tumor, such as B cells and T cells, as well as an uptick in immune-related activity in the cancer cells themselves.

Further experiments identified this signal as CXCL11, a protein secreted by immune cells that recruits T cells to fight tumors and infections. When researchers cultured hormone receptor-positive breast cancer cells without estrogen, a state in which they typically grow poorly, the cells thrived with the addition of CXCL11. They found similar results when they co-cultured breast cancer cells with T cells.

The results suggest that T cells within hormone receptor-positive, ED-resistant tumors are a double-edged sword. Although the CXCL11 they produce spurs cancer growth, it also summons T cells to the tumor site that could potentially serve as cancer fighters. While hormone receptor-positive breast cancers have long been considered immunologically cold, ED-sensitive tumors fit that pattern whereas ED-resistant tumors appear to have significantly more T cells.

Researchers said they plan to test in a future clinical trial whether these tumors may be more responsive to immunotherapies. They also said doctors may eventually use CXCL11 as a biomarker to signal which hormone receptor-positive breast cancers might respond to immunotherapies.

The study was funded by the National Cancer Institute, the Department of Defense, the Cancer Prevention and Research Institute of Texas, the Susan G. Komen Breast Cancer Foundation, and the Breast Cancer Research Foundation.