Researchers at Massachusetts General Hospital revealed that fibrosis, basically an excess of connective tissue in an organ, may block the effectiveness of immunotherapies against metastatic breast cancer. One of the main focus points for the team was to determine how the physical features of tumors can impede the effectiveness of cancer therapies.
“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”, noted Ivy Chen, Ph.D., a post-doctoral fellow at MGH.
Treatment-resistant tumors, or desmoplastic, are characterized by an overgrowth of connective tissue, which can block or even repel cancer-killing T cells from entering tumors, as well as inhibiting the effectiveness of traditional anti-cancer therapies. Previous studies have shown that the CXCL12/CXCR4 signaling pathway plays an important role in regulating these immune cells.
Investigators made several important discoveries along the way, some leading to offer Plerixafor as a solution, a drug approved to mobilize blood system stem cells in the treatment of lymphoma and multiple myeloma patients. It can decrease fibrosis in both primary and metastatic breast tumors and improve response to immunotherapy in mouse models.
Using The Cancer Genome Atlas database it was established that CXCL12/CX1CR4 signaling forced the exclusion of cancer-fighting CD8 T cells from human breast cancers. Then, a comparative analysis of samples from primary and metastatic breast tumors from the same patients confirmed that CXCR4 expression correlated with high levels of desmoplasia and expression of immunosuppressive proteins in all subtypes of breast cancer.
Blocking the CXCR4 gene decreased the formation of spontaneous metastases in the lung, one of the most common sites for metastatic breast cancer. Treatment also made mouse subjects more sensitive to immune checkpoint blockers, a common form of immunotherapy that has transformed the treatment of a number of malignancies.
Co-author Robert Langer, ScD, Koch Institute Professor at Massachusetts Institute of Technology, added: “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“.
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