DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Blocking CXCR4 Reduces Tumor Fibrosis and Sensitizes Metastatic Breast Cancer to Immunotherapy

Posted May 31, 2019
Rakesh Jain, Ph.D., Massachusetts General Hospital

Rakesh Jain, Ph.D., Cold Spring Harbor Laboratory
Dr. Rakesh Jain

Although immune checkpoint blockade (ICB) therapy has demonstrated clinical benefit in multiple malignancies, metastatic breast cancer patients have only shown modest response rates. A common theme observed in malignancies that do not respond well to ICB therapy is the presence of dense fibrous tissue, termed desmoplasia, surrounding the primary or metastatic tumor. Desmoplastic tumors are enriched with cancer-associated fibroblasts (CAFs), a type of cell that deposits a dense fibrous matrix around the tumor that not only inhibits drug delivery to the site of tumor cells, but also creates an immunosuppressive environment, preventing tumor killing cytotoxic T-lymphocytes (CTLs) from gaining access to the tumor. Although desmoplasia and its immunosuppressive effects on primary tumors are well known, its role in promoting immune suppression in metastatic lesions, particularly breast cancer, has not been studied. Therefore, with a Fiscal Year 2009 Breast Cancer Research Program Innovator Award, Dr. Rakesh Jain sought to more clearly define the mechanisms underlying desmoplasia-mediated immune suppression in breast cancer and to determine whether inhibition of activated signaling pathways could be exploited to improve metastatic breast cancer response rates to ICB therapy.

As described in a recent PNAS article, Dr. Jain’s team performed an unbiased screen of The Cancer Genome Atlas to look for genes associated with an immunosuppressive phenotype, particularly those that would lead to the exclusion of CTLs. This screening found that a ligand (CXCL12) for a chemokine receptor known to be associated with causing immunosuppression, CXCR4, was upregulated in breast cancer. Confirming these results, the team analyzed paired primary and metastatic breast cancer tumor samples and found that CXCR4 was upregulated in both liver and lung metastases, as well as in the primary tumor. More importantly, CXCR4 expression was upregulated in both cancer cells and stromal cells and correlated with a shorter progression-free survival in patients. Examining the immune profile of the primary and metastatic samples, the team found that metastatic lesions expressing CXCR4 were devoid of CTLs, but highly enriched in CAFs.

To determine whether inhibition of CXCR4 signaling could alleviate the immunosuppressive phenotype, Dr. Jain and his team gave Plerixafor, a U.S. Food and Drug Administration (FDA)-approved CXCR4 inhibitor, to mouse models of HER2+ or triple-negative breast cancer (TNBC). Tumors from mice treated with Plerixafor contained fewer CAFs, a greater number of CTLs, and reduced fibrosis compared to control treated animals. Plerixafor treatment also relaxed the immunosuppressive tumor microenvironment as evidenced by reduced desmoplastic and pro-metastatic markers and increased anti-tumor immune markers. More importantly, Plerixafor treatment resulted in a two-fold reduction in the number of spontaneous lung metastases that formed in the TNBC mouse model and significantly increased overall survival.

The team next treated mice with established metastatic lesions from models of HER2+ or TNBC with Plerixafor or Plerixafor plus ICB therapy (combination therapy) to determine whether CXCR4 blockade could sensitize breast cancer tumors to ICB therapy. In mice treated with either Plerixafor alone or the combination therapy, fewer and significantly smaller lung metastases were observed compared to those in the control-treated animals. In addition, metastatic lung tumors from treated animals were found to be less fibrotic and had increased numbers of CTLs in the surrounding stroma. Combination treatment, however, produced a stronger reversal of the immunosuppressive phenotype compared to Plerixafor alone. Metastatic tumors from mice treated with combination therapy displayed increased expression of several markers of T cell activity and had a reduced expression of immunosuppressive markers. Combination treatment was also found to extend median survival by 76% in the HER2+ model and by 35% in a TNBC model compared to controls. In both the HER2+ and TNBC metastatic mouse models, combination therapy increased the number of long-term survivors. In one model of metastatic TNBC, 57% of combination therapy treated animals were disease-free for more than 6 months after treatment initiation extending the median survival by 35 days over control-treated animals and nearly doubling the 29% cure rate for ICB treatment alone.

Dr. Jain and his team have shown for the first time that CAF-mediated CXCR4 signaling promotes a desmoplastic immunosuppressive environment surrounding both primary and metastatic lesions in animal models recapitulating multiple subtypes of breast cancer. The group demonstrated a proof-of-concept therapy, using a current FDA-approved agent, which targets this molecular pathway to sensitize metastatic breast cancers to ICB therapy. Although additional studies are needed, Dr. Jain’s work has the potential to be rapidly translated into the clinic, where it could be used to help metastatic breast cancer patients.

 

Publication:

Chen IX, Chauhan VP, Posada J, et al. 2019. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. PNAS 116(10):4558-4566.

Link:

Public and Technical Abstracts: Strategies for Personalized Treatment of Metastatic Breast Cancer: Vascular Normalization and Sensitization

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Last updated Friday, May 31, 2019