Up to 20% of hormone receptor-positive breast cancers do not respond to anti-oestrogen therapies, and a study led by researchers at the University of Texas (UT) Southwestern in the US now suggests that a protein secreted by immune cells within these tumours is what causes them to grow, even in the absence of oestrogen.
“Our findings on the role of the tumour immune microenvironment in endocrine resistance point to new therapeutic strategies to overcome resistance and improve outcomes for patients,” said Ariella Hanker, Ph.D, Associate Professor in the Harold C Simmons Comprehensive Cancer Centre and of Internal Medicine at UT Southwestern.
Oncology News Today reports that Hanker co-led the study with Carlos Arteaga, MD, director of the Simmons Cancer Centre and Associate Dean of Oncology Programmes, and first author Fabiana Napolitano, MD, Ph.D, a former member of the Arteaga Lab.
Nearly 80% of breast cancers are hormone receptor-positive and thus rely on oestrogen to multiply and survive.
Treatment of these cancers is typically based on depriving them of oestrogen through various means, like drugs that inhibit oestrogen 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.
Why these hormone receptor-positive cancers resist anti-oestrogen therapies hasn’t been clear, Hanker said. To answer this question, she and her colleagues looked at 173 tumour samples from Vanderbilt University Medical Centre, UT Southwestern, and Parkland Health.
They compared those that responded to oestrogen-depriving (ED) treatment with those that had become resistant, and found a significant increase in gene expression for various immune pathways in the resistant tumours. These findings suggest the presence of immune cells within the tumour, such as B cells and T cells, as well as an uptick in immune-related activity in the cancer cells themselves.
Examining similar tissue samples collected before and after patients received ED therapy showed that the therapy itself appeared to spur these immune pathways, increasing the infiltration of activated immune cells into tumours – but only in the ED-resistant samples.
This suggests that anti-oestrogen therapy might cause cells within the tumour to release a chemical signal summoning the immune cells to the cancer site.
Further experiments identified this signal as CXCL11, a protein secreted by immune cells that recruits T cells to fight tumours and infections. When the researchers cultured hormone receptor-positive breast cancer cells without oestrogen – a state in which they typically grow poorly – they thrived with the addition of CXCL11.
They found similar results when they co-cultured breast cancer cells with T cells.
“This study is a good bedside-to-bench example of how starting from tumours in patients treated with oestrogen suppression can inform mechanistic discovery in the laboratory that, in turn, can inform new biology and treatment directions for patients with breast cancer,” said Arteaga, who also holds the Annette Simmons Distinguished University Chair in Breast Cancer Research.
Combined, these results suggest that T cells within hormone receptor-positive, ED-resistant tumours are a double-edged sword. Although the CXCL11 they produce spurs cancer growth, it also summons T cells to the tumour site that could potentially serve as cancer fighters, Hanker observed.
Hormone receptor-positive breast cancers have long been considered immunologically “cold”, meaning that immunotherapies aren’t effective because they lack active immune cells.
While this is true for the ED-sensitive tumours, ED-resistant tumours appear to have significantly more T cells. Thus, they may be more responsive to immunotherapies, an idea Hanker and her colleagues plan to test in a future clinical trial.
“Eventually, doctors may use CXCL11 as a biomarker to signal which hormone receptor-positive breast cancers might respond to immunotherapies,” she said.
The research was published in The Journal of Clinical Investigation.
Oncology News Today article – Study identifies why some breast cancers evade treatment (Open access)
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