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Intratumoral HLA-DR(−)/CD33(+)/CD11b(+) Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer
Capecitabine-based neoadjuvant chemoradiation therapy (nCRT) is currently the mainstay of treatment for locally advanced rectal cancer (LARC), prior to surgical tumor removal. While response to this treatment is partial, it carries significant risk of side effects. As of today, there is no accepted...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435035/ https://www.ncbi.nlm.nih.gov/pubmed/32903466 http://dx.doi.org/10.3389/fonc.2020.01375 |
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author | Hasnis, Erez Dahan, Aviva Khoury, Wissam Duek, Daniel Fisher, Yael Beny, Alex Shaked, Yuval Chowers, Yehuda Half, Elizabeth E. |
author_facet | Hasnis, Erez Dahan, Aviva Khoury, Wissam Duek, Daniel Fisher, Yael Beny, Alex Shaked, Yuval Chowers, Yehuda Half, Elizabeth E. |
author_sort | Hasnis, Erez |
collection | PubMed |
description | Capecitabine-based neoadjuvant chemoradiation therapy (nCRT) is currently the mainstay of treatment for locally advanced rectal cancer (LARC), prior to surgical tumor removal. While response to this treatment is partial, it carries significant risk of side effects. As of today, there is no accepted model to predict tumor response, and allow for patient stratification. The level of circulating Myeloid-derived suppressor cells (MDSCs), a subpopulation of early myeloid cells (EMCs), has been shown to correlate with prognosis and response to therapy in advanced colon cancer, but their role in LARC is not clear. We sought to study the effect of intratumoral and circulating levels of different EMCs subpopulations including MDSCs on response to nCRT. We analyzed tumor, normal mucosa, and peripheral blood samples from 25 LARC patients for their different EMCs subpopulation before and after nCRT, and correlated them with degree of pathologic response, as determined postoperatively. In addition, we compared LARC patient to 10 healthy donors and 6 metastatic patients. CD33(+)HLA-DR(−)CD16(−)CD11b(+)EMCs in the circulation of LARC patients were found to inhibit T-cell activation. Furthermore, elevated levels of CD33(+)HLA-DR(−) myeloid cells were found in the tumor relative to normal mucosa, but not in the circulation when compared to healthy subjects. Moreover, intratumoral, but not circulating levels of MDSCs correlated with clinical stage and response to therapy in patients treated with nCRT, with high levels of MDSCs significantly predicting poor response to nCRT. Importantly, therapy by itself, had significant differential effects on MDSC levels, leading to increased circulating MDSCs, concomitantly with decreasing intratumoral MDSCs. Our results suggest that high levels of intratumoral, but not circulating MDSCs may confer drug resistance due to immunomodulatory effects, and serve as a biomarker for patient stratification and decision-making prior to nCRT. |
format | Online Article Text |
id | pubmed-7435035 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74350352020-09-03 Intratumoral HLA-DR(−)/CD33(+)/CD11b(+) Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Hasnis, Erez Dahan, Aviva Khoury, Wissam Duek, Daniel Fisher, Yael Beny, Alex Shaked, Yuval Chowers, Yehuda Half, Elizabeth E. Front Oncol Oncology Capecitabine-based neoadjuvant chemoradiation therapy (nCRT) is currently the mainstay of treatment for locally advanced rectal cancer (LARC), prior to surgical tumor removal. While response to this treatment is partial, it carries significant risk of side effects. As of today, there is no accepted model to predict tumor response, and allow for patient stratification. The level of circulating Myeloid-derived suppressor cells (MDSCs), a subpopulation of early myeloid cells (EMCs), has been shown to correlate with prognosis and response to therapy in advanced colon cancer, but their role in LARC is not clear. We sought to study the effect of intratumoral and circulating levels of different EMCs subpopulations including MDSCs on response to nCRT. We analyzed tumor, normal mucosa, and peripheral blood samples from 25 LARC patients for their different EMCs subpopulation before and after nCRT, and correlated them with degree of pathologic response, as determined postoperatively. In addition, we compared LARC patient to 10 healthy donors and 6 metastatic patients. CD33(+)HLA-DR(−)CD16(−)CD11b(+)EMCs in the circulation of LARC patients were found to inhibit T-cell activation. Furthermore, elevated levels of CD33(+)HLA-DR(−) myeloid cells were found in the tumor relative to normal mucosa, but not in the circulation when compared to healthy subjects. Moreover, intratumoral, but not circulating levels of MDSCs correlated with clinical stage and response to therapy in patients treated with nCRT, with high levels of MDSCs significantly predicting poor response to nCRT. Importantly, therapy by itself, had significant differential effects on MDSC levels, leading to increased circulating MDSCs, concomitantly with decreasing intratumoral MDSCs. Our results suggest that high levels of intratumoral, but not circulating MDSCs may confer drug resistance due to immunomodulatory effects, and serve as a biomarker for patient stratification and decision-making prior to nCRT. Frontiers Media S.A. 2020-08-12 /pmc/articles/PMC7435035/ /pubmed/32903466 http://dx.doi.org/10.3389/fonc.2020.01375 Text en Copyright © 2020 Hasnis, Dahan, Khoury, Duek, Fisher, Beny, Shaked, Chowers and Half. 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 | Oncology Hasnis, Erez Dahan, Aviva Khoury, Wissam Duek, Daniel Fisher, Yael Beny, Alex Shaked, Yuval Chowers, Yehuda Half, Elizabeth E. Intratumoral HLA-DR(−)/CD33(+)/CD11b(+) Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer |
title | Intratumoral HLA-DR(−)/CD33(+)/CD11b(+) Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer |
title_full | Intratumoral HLA-DR(−)/CD33(+)/CD11b(+) Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer |
title_fullStr | Intratumoral HLA-DR(−)/CD33(+)/CD11b(+) Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer |
title_full_unstemmed | Intratumoral HLA-DR(−)/CD33(+)/CD11b(+) Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer |
title_short | Intratumoral HLA-DR(−)/CD33(+)/CD11b(+) Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer |
title_sort | intratumoral hla-dr(−)/cd33(+)/cd11b(+) myeloid-derived suppressor cells predict response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435035/ https://www.ncbi.nlm.nih.gov/pubmed/32903466 http://dx.doi.org/10.3389/fonc.2020.01375 |
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