Fibrosis-Targeting Drugs May Improve Immunotherapy Response in Breast Cancer

New research has revealed a correlation between fibrosis, CXCR4 expression, and immunosuppression in metastatic breast cancer, according to a study published in PNAS. The findings could lead to new therapeutic approaches that could improve the efficacy of immunotherapy in patients with the disease.
According to the study, many treatment-resistant tumors are highly fibrotic. Fibrosis, which is the overgrowth of connective tissue, can inhibit the efficacy of immunotherapies against breast cancer. The researchers suggested that drugs targeting fibrosis may help improve the response to immunotherapy in these patients.
The study provided insight into understanding how the physical features of tumors can block the response to cancer therapies and identified the role of the CXCR4 signaling pathway in resistance to immunotherapies. In an examination of paired biopsies of primary and metastatic breast tumors from the same patients, the researchers found that CXCR4 expression was linked to high levels of fibrosis and expression of immunosuppressive proteins in all subtypes of breast cancer.
“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,” lead author Ivy Chen, PhD, post-doctoral fellow in the Edwin L Steele Laboratories for Tumor Biology in the Massachusetts General Hospital Department of Radiation Oncology, 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.”
Plerixafor, a drug that inhibits CXCR4 and is approved for lymphoma and multiple myeloma, reduced fibrosis and the expression of profibrotic and immunosuppressive genes in experiments using mouse models. According to the researchers, these immunosuppressive effects were dependent on CXCR signaling in fibroblasts, cells that produce fibrosis and promote immunosuppression. In addition, CXCR4 blockade sensitized 3 mouse models to immune checkpoint blockers, indicating the potential for CXCR4 inhibition to improve treatment responses.
“Our findings suggest that fibrosis-targeting drugs, such as plerixafor, may be able to benefit breast cancer patients with late-stage, metastatic disease,” senior author Rakesh Jain, PhD said.
Because not all metastatic breast cancers respond to immunotherapy, the findings could have significant therapeutic implications for patients whose tumors are treatment resistant. The next step would be clinical trials to test the efficacy of combining CXCR4 inhibition with immune checkpoint blockade for this patient population, Dr Jain concluded.
Blocking pro-fibrosis signaling pathway may improve immunotherapy of metastatic breast cancer [news release]. Massachusetts General Hospital. Accessed January
28, 2019.

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