Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer
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 m...
| Main Authors: | , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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National Academy of Sciences
2020
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| Online Access: | https://hdl.handle.net/1721.1/125038 |
| _version_ | 1826204974396211200 |
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| author | 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. |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering 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. |
| author_sort | Chen, Ivy Xiaoyu |
| collection | MIT |
| description | 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 |
| first_indexed | 2024-09-23T13:04:15Z |
| format | Article |
| id | mit-1721.1/125038 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:04:15Z |
| publishDate | 2020 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1250382022-09-28T11:52:22Z Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer 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. Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT 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 United States. National Cancer Institute (Grant P01-CA080124) United States. National Cancer Institute (Grant R01-CA098706) United States. National Cancer Institute (Grant R01-CA208205) United States. National Cancer Institute (Grant U01- CA224348) National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowship F32- CA073479) S. Leslie Misrock Frontier Research Fund for Cancer Nanotechnology (Misrock Fellowship) 2020-05-06T14:06:26Z 2020-05-06T14:06:26Z 2019-01 2018-09 2019-09-09T13:29:05Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 https://hdl.handle.net/1721.1/125038 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. en http://dx.doi.org/10.1073/pnas.1815515116 Proceedings of the National Academy of Sciences 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. application/pdf National Academy of Sciences PNAS |
| spellingShingle | 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. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer |
| title | Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer |
| title_full | Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer |
| title_fullStr | Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer |
| title_full_unstemmed | Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer |
| title_short | Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer |
| title_sort | blocking cxcr4 alleviates desmoplasia increases t lymphocyte infiltration and improves immunotherapy in metastatic breast cancer |
| url | https://hdl.handle.net/1721.1/125038 |
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