Contributed by Rakesh K. Jain, December 7, 2018 (sent for review September 10, 2018; reviewed by Douglas T. Fearon and George W. Sledge)
Although immune checkpoint blockade (ICB) along with nab-paclitaxel has increased progression-free survival in triple-negative breast cancer patients, a large fraction of metastatic breast cancer (mBC) patients do not benefit from ICBs. The presence of a fibrotic tumor microenvironment can suppress the immune response to cancer. Here we found fibrosis and immunosuppression in both primary and metastatic breast cancer lesions. We show that targeting CXCR4/CXCL12 signaling, using plerixafor, an Food and Drug Administration-approved drug, reduces fibrosis, alleviates immunosuppression, and significantly enhances the efficacy of immune checkpoint blockers in preclinical models of mBC. Our findings provide a deeper understanding of mechanisms by which desmoplasia promotes immunosuppression in mBC and suggest a clinically translatable approach that can be combined with immunotherapy in patients to enhance therapeutic response.
Metastatic breast cancers (mBCs) are largely resistant to immune checkpoint blockade, but the mechanisms remain unclear. Primary breast cancers are characterized by a dense fibrotic stroma, which is considered immunosuppressive in multiple malignancies, but the stromal composition of breast cancer metastases and its role in immunosuppression are largely unknown. Here we show that liver and lung metastases of human breast cancers tend to be highly fibrotic, and unlike primary breast tumors, they exclude cytotoxic T lymphocytes (CTLs). Unbiased analysis of the The Cancer Genome Atlas database of human breast tumors revealed a set of genes that are associated with stromal T-lymphocyte exclusion. Among these, we focused on CXCL12 as a relevant target based on its known roles in immunosuppression in other cancer types. We found that the CXCL12 receptor CXCR4 is highly expressed in both human primary tumors and metastases. To gain insight into the role of the CXCL12/CXCR4 axis, we inhibited CXCR4 signaling pharmacologically and found that plerixafor decreases fibrosis, alleviates solid stress, decompresses blood vessels, increases CTL infiltration, and decreases immunosuppression in murine mBC models. By deleting CXCR4 in αSMA+ cells, we confirmed that these immunosuppressive effects are dependent on CXCR4 signaling in αSMA+ cells, which include cancer-associated fibroblasts as well as other cells such as pericytes. Accordingly, CXCR4 inhibition more than doubles the response to immune checkpoint blockers in mice bearing mBCs. These findings demonstrate that CXCL12/CXCR4-mediated desmoplasia in mBC promotes immunosuppression and is a potential target for overcoming therapeutic resistance to immune checkpoint blockade in mBC patients.
Author contributions: I.X.C., V.P.C., M.R.N., P.A., P.H., R.L., and R.K.J. designed research; I.X.C., V.P.C., J.P., M.R.N., M.W.W., and P.A. performed research; I.X.C., J.P., P.H., N.L., R.L., and R.K.J. contributed new reagents/analytic tools; I.X.C., V.P.C., J.P., M.R.N., M.W.W., P.A., N.L., and R.K.J. analyzed data; and I.X.C., V.P.C., M.R.N., R.L., and R.K.J. wrote the paper.
Reviewers: D.T.F., Cold Spring Harbor Laboratory; and G.W.S., Stanford University Medical Center.
Conflict of interest statement: R.K.J. received an honorarium from Amgen; consultant fees from Merck, Ophthotech, Pfizer, SPARC, SynDevRx, and XTuit; owns equity in Enlight, Ophthotech, and SynDevRx; and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study. R.K.J. and D.T.F. are co-authors of a 2018 National Cancer Institute-Tumor Immune Microenvironment Workshop meeting report.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1815515116/-/DCSupplemental.
Published under the PNAS license.
See related content: