Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer
Open accessAbstract
Significance: 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.
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Interference with the action of CXCL12 produced by CAFs promotes T cell-mediated tumour control.
“Interference with the action of CXCL12 produced by CAFs promotes T cell-mediated tumour control16,121,122”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [122]
The CXCR4 inhibition results (page not provided) show increased cytotoxic T-cell infiltration and reduced regulatory T cells, while the section on response to immune checkpoint blockade links CXCR4 blockade to improved T-cell access and delayed metastatic growth. The copy does not establish that the CXCL12 being interfered with was produced by CAFs; it tests CXCR4 blockade rather than specifically blocking CAF-derived CXCL12. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBetter tumor blood vessels support adaptive antitumor immunity by helping tumor-infiltrating lymphocytes traffic and relocate, which improves results of immunotherapies such as immune checkpoint blockade.
“An improved vascular network favors adaptive antitumor immunity by promoting trafficking and re-localization of tumor-infiltrating lymphocytes (TILs), leading to improved outcomes of various immunotherapies, including immune checkpoint blockade (ICB) (15-20).”
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- Authors
- Chen, I. X., Chauhan, V. P., Posada, J., Ng, M. R., Wu, M. W., Adstamongkonkul, P., Huang, P., Lindeman, N., Langer, R., & Jain, R. K.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
- Corresponding author
- Jain, Rakesh K.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-01-30
- Volume
- 116
- Issue
- 10
- Pages
- 4558-4566
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6410779
- OpenAlex
- W2911526204
- Cited by
- 406
- References
- 58
- Citations by year
- 2026: 30 · 2025: 45 · 2024: 38 · 2023: 66 · 2022: 68 · 2021: 76 · 2020: 58 · 2019: 25
- FWCI
- 24.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- HHS | NIH | National Cancer Institute (P01-CA080124, R01-CA098706, R01-CA208205, U01-CA224348, R35-CA197743)
- U.S. Department of Defense (W81XWH-10-1-0016, W81XWH-14-1-0034)
- National Institute of Health (F32-CA073479, T32HL007627)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- CXCR4, CXCL12, plerixafor, desmoplasia, immunosuppression, T cell infiltration, immune checkpoint blockade, metastatic breast cancer, triple-negative breast cancer, nab-paclitaxel, combination immunotherapy
- MeSH terms
- Animals, Breast Neoplasms, Female, Humans, Immunotherapy, Neoplasm Metastasis, T-Lymphocytes, Receptors, CXCR4, Mice, Tumor Microenvironment
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