Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer
| Autor: | Michelle W. Wu, Rakesh K. Jain, Jessica M. Posada, Neal I. Lindeman, Pichet Adstamongkonkul, Ivy X. Chen, Robert Langer, Peigen Huang, Vikash P. Chauhan, Mei Rosa Ng |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Receptors CXCR4 Stromal cell T-Lymphocytes medicine.medical_treatment Breast Neoplasms Mice 03 medical and health sciences 0302 clinical medicine Breast cancer Commentaries Tumor Microenvironment medicine Animals Humans Neoplasm Metastasis Tumor microenvironment Multidisciplinary business.industry Immunosuppression Immunotherapy medicine.disease Metastatic breast cancer Immune checkpoint Desmoplasia 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Female medicine.symptom business |
| Zdroj: | Proceedings of the National Academy of Sciences. 116:4558-4566 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1815515116 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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