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PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density
Post-partum breast cancer patients, or breast cancer patients diagnosed within 10 years of last childbirth, are ~3–5 times more likely to develop metastasis in comparison to non-post-partum, or nulliparous, patients. Additionally, post-partum patients have increased tumor-associated lymphatic vessel...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579890/ https://www.ncbi.nlm.nih.gov/pubmed/31244852 http://dx.doi.org/10.3389/fimmu.2019.01313 |
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author | Tamburini, Beth A. Jirón Elder, Alan M. Finlon, Jeffrey M. Winter, Andrew B. Wessells, Veronica M. Borges, Virginia F. Lyons, Traci R. |
author_facet | Tamburini, Beth A. Jirón Elder, Alan M. Finlon, Jeffrey M. Winter, Andrew B. Wessells, Veronica M. Borges, Virginia F. Lyons, Traci R. |
author_sort | Tamburini, Beth A. Jirón |
collection | PubMed |
description | Post-partum breast cancer patients, or breast cancer patients diagnosed within 10 years of last childbirth, are ~3–5 times more likely to develop metastasis in comparison to non-post-partum, or nulliparous, patients. Additionally, post-partum patients have increased tumor-associated lymphatic vessels and LN involvement, including when controlled for size of the primary tumor. In pre-clinical, immune-competent, mouse mammary tumor models of post-partum breast cancer (PPBC), tumor growth and lymphogenous tumor cell spread occur more rapidly in post-partum hosts. Here we report on PD-L1 expression by lymphatic endothelial cells and CD11b+ cells in the microenvironment of post-partum tumors, which is accompanied by an increase in PD-1 expression by T cells. Additionally, we observed increases in PD-L1 and PD-1 in whole mammary tissues during post-partum mammary gland involution; a known driver of post-partum tumor growth, invasion, and metastasis in pre-clinical models. Importantly, implantation of murine mammary tumor cells during post-partum mammary gland involution elicits a CD8+ T cell population that expresses both the co-inhibitory receptors PD-1 and Lag-3. However, upon anti-PD-1 treatment, during post-partum mammary gland involution, the involution-initiated promotional effects on tumor growth are reversed and the PD-1, Lag-3 double positive population disappears. Consequently, we observed an expansion of poly-functional CD8+ T cells that produced both IFNγ and TNFα. Finally, lymphatic vessel frequency decreased significantly following anti-PD-1 suggesting that anti-PD-1/PD-L1 targeted therapies may have efficacy in reducing tumor growth and dissemination in post-partum breast cancer patients. |
format | Online Article Text |
id | pubmed-6579890 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65798902019-06-26 PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density Tamburini, Beth A. Jirón Elder, Alan M. Finlon, Jeffrey M. Winter, Andrew B. Wessells, Veronica M. Borges, Virginia F. Lyons, Traci R. Front Immunol Immunology Post-partum breast cancer patients, or breast cancer patients diagnosed within 10 years of last childbirth, are ~3–5 times more likely to develop metastasis in comparison to non-post-partum, or nulliparous, patients. Additionally, post-partum patients have increased tumor-associated lymphatic vessels and LN involvement, including when controlled for size of the primary tumor. In pre-clinical, immune-competent, mouse mammary tumor models of post-partum breast cancer (PPBC), tumor growth and lymphogenous tumor cell spread occur more rapidly in post-partum hosts. Here we report on PD-L1 expression by lymphatic endothelial cells and CD11b+ cells in the microenvironment of post-partum tumors, which is accompanied by an increase in PD-1 expression by T cells. Additionally, we observed increases in PD-L1 and PD-1 in whole mammary tissues during post-partum mammary gland involution; a known driver of post-partum tumor growth, invasion, and metastasis in pre-clinical models. Importantly, implantation of murine mammary tumor cells during post-partum mammary gland involution elicits a CD8+ T cell population that expresses both the co-inhibitory receptors PD-1 and Lag-3. However, upon anti-PD-1 treatment, during post-partum mammary gland involution, the involution-initiated promotional effects on tumor growth are reversed and the PD-1, Lag-3 double positive population disappears. Consequently, we observed an expansion of poly-functional CD8+ T cells that produced both IFNγ and TNFα. Finally, lymphatic vessel frequency decreased significantly following anti-PD-1 suggesting that anti-PD-1/PD-L1 targeted therapies may have efficacy in reducing tumor growth and dissemination in post-partum breast cancer patients. Frontiers Media S.A. 2019-06-11 /pmc/articles/PMC6579890/ /pubmed/31244852 http://dx.doi.org/10.3389/fimmu.2019.01313 Text en Copyright © 2019 Tamburini, Elder, Finlon, Winter, Wessells, Borges and Lyons. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Tamburini, Beth A. Jirón Elder, Alan M. Finlon, Jeffrey M. Winter, Andrew B. Wessells, Veronica M. Borges, Virginia F. Lyons, Traci R. PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density |
title | PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density |
title_full | PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density |
title_fullStr | PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density |
title_full_unstemmed | PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density |
title_short | PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density |
title_sort | pd-1 blockade during post-partum involution reactivates the anti-tumor response and reduces lymphatic vessel density |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579890/ https://www.ncbi.nlm.nih.gov/pubmed/31244852 http://dx.doi.org/10.3389/fimmu.2019.01313 |
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