The researchers found that fibrosis — the excessive growth of connective tissue inside tumors — prevented cancer-fighting T-cells from entering tumors and largely impaired immune checkpoint inhibitors from effectively eliminating metastatic breast cancer.
Primary breast cancer tumors contain a dense core of fibrotic tissue that has been shown in other types of tumors to suppress the activity of immune cells against cancer cells, rendering current cancer immunotherapies ineffective.
Once cancer has metastasized, the composition of tumor masses and their interaction with the immune system remain unclear. One aspect that is clear, though, is that metastatic breast cancer is extremely resistant to current cancer therapies, which is linked to poor survival outcomes.
“Improving the survival of patients with metastatic breast cancer remains a significant challenge; and while immunotherapy, which harnesses the power of the immune system against cancer, has shown some promise, it remains less effective against metastatic breast cancer,” Ivy Chen, PhD, a post-doctoral fellow at the Massachusetts General Hospital and lead author of the study, said in a press release.
“While fibrosis has been extensively studied in primary breast tumors, little is known about the level of fibrosis and its role in immunosuppression in metastatic lesions,” Chen added.
In other types of tumors, the CXCL12/CXCR4 signaling cascade — a chemical pathway involved in the regulation of immune cells — plays a key role in tumor resistance to immunotherapies.
The research team studied the composition of liver and lung metastases from breast cancer patients, and found that they contained highly fibrotic tissue that prevented T-cells from entering the tumor masses.
Moreover, after analyzing The Cancer Genome Atlas — an online database of human cancers — investigators found the CXCL12/CXCR4 signaling pathway was involved in the exclusion of killer T-cells from breast cancer masses in patients.
These findings were later confirmed by biopsies from breast cancer primary tumors and metastases that contained high levels of CXCR4.
To understand how CXCL12/CXCR4 regulates the exclusion of immune cells from tumor masses, researchers blocked the pathway using plerixafor, a treatment that inhibits CXCR4, in a mouse model of metastatic breast cancer.
Results showed that plerixafor treatment — sold under the brand name Mozobil by Sanofi Genzyme — reduced tumor fibrosis, increased T-cell infiltration, and decreased cancer cell resistance to immunotherapy in mice. Further experiments in mice, genetically engineered to be unable to produce CXCR4, showed that their response to immune checkpoint blockers increased by more than two-fold.
“Given that CXCR4 signaling is a key driver for tumor fibrosis and immunosuppression, it is reasonable to speculate that combining CXCR4 inhibition could potentially unleash further benefits of immunotherapy in (metastatic breast cancer) patients,” the scientists wrote.
“Our findings provide the necessary data and rationale for clinical trials to test the efficacy of combining CXCR4 inhibition using plerixafor … with immune checkpoint blockade for metastatic breast cancer patients,” said Rakesh Jain, oncology professor at Harvard Medical School and the study’s senior author.
Added the study’s co-author Robert Langer, ScD, a professor at Massachusetts Institute of Technology: “With more than 40,000 women dying from breast cancer annually in the U.S. alone, this work provides a rapidly translatable strategy and potential hope for these patients.”