New study identifies gene responsible for driving immunotherapy resistance in breast cancer

Immunotherapy drugs like pembrolizumab are helping transform cancer care by unlocking new ways to harness the power of our immune systems to treat cancer. But for these drugs to work, immune cells, particularly T cells, must first be able to detect and enter the tumour on their own. In many cancers, though, this immune infiltration is limited, making these drugs ineffective.

In a new study published in Biomarker Research, Nova Scotia-based researchers supported by the Marathon of Hope Cancer Centres Network (MOHCCN) have identified that a gene called THSD4 plays a central role in preventing T cells from entering tumours, driving resistance to immunotherapy in patients with hormone receptor-positive breast cancer.

“By studying large patient datasets, including samples from the MOHCCN’s Atlantic Cancer Consortium, we found that tumours with high levels of THSD4 had significantly fewer T cells, poorer survival outcomes and reduced response to the immunotherapy drug pembrolizumab,” says Dr. Paola Marcato, who led the study.

To better understand the relationship between THSD4 and T cell infiltration in tumours, the researchers combined genomic profiling with advanced immune analysis across patient samples and preclinical models. Their findings revealed that THSD4 acts as a mediator of immune exclusion, effectively creating a barrier that prevents cancer-fighting T cells from reaching the tumour.

Importantly, the team also demonstrated that this resistance may be reversible. In a mouse model of hormone receptor-positive breast cancer, reducing THSD4 levels led to increased T cell infiltration and significantly improved response to pembrolizumab, resulting in smaller tumours.

“By identifying THSD4 as a driver of T cell exclusion, we now have a clearer understanding of why some breast cancers do not respond to immunotherapy,” says Olivia Walker, first author on the study and PhD student in Dr. Marcato's lab. “This opens new opportunities to both predict response and develop strategies to overcome resistance.”

These findings have important implications for precision oncology, particularly in hormone receptor-positive breast cancer, which accounts for approximately 70% of all breast cancer cases but which is not routinely treated with immunotherapy. By measuring THSD4 levels, clinicians may be able to identify patients who are more likely to benefit from pembrolizumab—expanding access to immunotherapy while sparing others from unnecessary side effects and delays in receiving alternative treatments.

Beyond its role as a biomarker, THSD4 also represents a promising therapeutic target, as strategies aimed at reducing or blocking its activity could help “turn on” the immune response in tumours that are otherwise resistant, paving the way for new combination treatments that enhance the efficacy of immunotherapy and bring new hope to breast cancer patients.

“This study relied directly on the Marathon of Hope Cancer Centres Network, through which we obtained paired genomic, immune, and clinical information from early-stage breast cancer patients, allowing us to link THSD4 expression with T cell exclusion and outcomes in a real-world setting,” says Dr. Marcato. “MOHCCN funding and infrastructure made it possible for us to perform the large-scale transcriptomic profiling and multiplex immunofluorescence needed to discover and validate THSD4 as a mediator of immune suppression and immunotherapy resistance.”

Study

THSD4 is a novel mediator of T cell exclusion and anti-PD-1 resistance in hormone receptor-positive breast cancer

Authors

Olivia L Walker, Marie-Claire D Wasson, Vishnupriyan Kumar, Sarah Nersesian, Jaganathan Venkatesh, Vishnu V Vijayan, Lily Coates, Wasundara Fernando, Raj Pranap Arun, Hannah F Cahill, Elizabeth Baker, Margaret L Dahn, Drew Slauenwhite, Brianne M Cruickshank, Penelope Barnes, Modeline N Longjohn, Thomas James Belbin, Daniel Gaston , Gregory C Knapp, Jennifer Melvin, Shashi Gujar, Jeanette E Boudreau, Gillian Bethune, Paola Marcato

Funding

Sequencing of patient samples for this study was partially funded by the Marathon of Hope Cancer Centres Network, through the Atlantic Cancer Consortium. These samples are now part of the MOHCCN Gold Cohort, which means that in the future, other researchers may use these data to further their precision medicine studies.