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Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer

Author(s)
Chen, Ivy Xiaoyu; Chauhan, Vikash P.; Posada, Jessica; Ng, Mei R.; Wu, Michelle W.; Adstamongkonkul, Pichet; Huang, Peigen; Lindeman, Neal; Langer, Robert S; Jain, Rakesh K.; ... Show more Show less
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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Abstract
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. Keywords: tumor microenvironment; mnetastatic breast cancer; immune checkpoint blockade; tumor desmoplasia; carcinoma-associated fibroblasts
Date issued
2019-01
URI
https://hdl.handle.net/1721.1/125038
Department
David H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Chemical Engineering; Massachusetts Institute of Technology. Department of Biological Engineering
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Citation
Chen, Ivy X., et al. “Blocking CXCR4 Alleviates Desmoplasia, Increases T-Lymphocyte Infiltration, and Improves Immunotherapy in Metastatic Breast Cancer.” Proceedings of the National Academy of Sciences 116, 10 (March 2019): 4558–66.
Version: Final published version
ISSN
0027-8424
1091-6490

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