Cargando…

Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer

Overcoming local immunosuppression is critical for immunotherapy to produce robust anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) are key regulators of immunosuppressive networks and promote tumor progression. However, it remains unclear whether and how tumor-infiltrating MDSCs are s...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Jing, Sun, Hong-Wei, Yang, Yan-Yan, Chen, Hai-Tian, Yu, Xing-Juan, Wu, Wen-Chao, Xu, Yi-Tuo, Jin, Li-Lian, Wu, Xiao-Jun, Xu, Jing, Zheng, Limin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791142/
https://www.ncbi.nlm.nih.gov/pubmed/33414378
http://dx.doi.org/10.1038/s41392-020-00377-3
_version_ 1783633547814240256
author Chen, Jing
Sun, Hong-Wei
Yang, Yan-Yan
Chen, Hai-Tian
Yu, Xing-Juan
Wu, Wen-Chao
Xu, Yi-Tuo
Jin, Li-Lian
Wu, Xiao-Jun
Xu, Jing
Zheng, Limin
author_facet Chen, Jing
Sun, Hong-Wei
Yang, Yan-Yan
Chen, Hai-Tian
Yu, Xing-Juan
Wu, Wen-Chao
Xu, Yi-Tuo
Jin, Li-Lian
Wu, Xiao-Jun
Xu, Jing
Zheng, Limin
author_sort Chen, Jing
collection PubMed
description Overcoming local immunosuppression is critical for immunotherapy to produce robust anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) are key regulators of immunosuppressive networks and promote tumor progression. However, it remains unclear whether and how tumor-infiltrating MDSCs are shaped in response to anti-PD-1 treatment and what their impact on therapeutic efficacy is in colorectal cancer (CRC). In this study, the levels of infiltrating MDSCs were significantly higher in the non-responding organoids and were selectively reduced in the responding group, with MDSCs showing increased apoptosis and attenuated functional activity after anti-PD-1 treatment. A negative correlation between T-cell activation and MDSC function was also observed in fresh human CRC tissues. Mechanistic studies revealed that autocrine IFN-α/β upregulated TRAIL expression on activated T cells to elicit MDSC apoptosis via the TRAIL–DR5 interaction and acted synergistically with TNF-α to inhibit MDSC function of suppressing the T-cell response through the JNK-NMDAR-ARG-1 pathway. Moreover, blockade of IFN-α/β and TNF-α abolished the therapeutic efficacy of anti-PD-1 treatment by preserving the frequency and suppressive activity of infiltrating MDSCs in a CRC mouse model. This result suggested that reprogramming MDSCs by IFN-α/β and TNF-α from activated T cells was necessary for successful anti-PD-1 treatment and might serve as a novel strategy to improve the response and efficacy of anticancer therapy.
format Online
Article
Text
id pubmed-7791142
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-77911422021-01-15 Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer Chen, Jing Sun, Hong-Wei Yang, Yan-Yan Chen, Hai-Tian Yu, Xing-Juan Wu, Wen-Chao Xu, Yi-Tuo Jin, Li-Lian Wu, Xiao-Jun Xu, Jing Zheng, Limin Signal Transduct Target Ther Article Overcoming local immunosuppression is critical for immunotherapy to produce robust anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) are key regulators of immunosuppressive networks and promote tumor progression. However, it remains unclear whether and how tumor-infiltrating MDSCs are shaped in response to anti-PD-1 treatment and what their impact on therapeutic efficacy is in colorectal cancer (CRC). In this study, the levels of infiltrating MDSCs were significantly higher in the non-responding organoids and were selectively reduced in the responding group, with MDSCs showing increased apoptosis and attenuated functional activity after anti-PD-1 treatment. A negative correlation between T-cell activation and MDSC function was also observed in fresh human CRC tissues. Mechanistic studies revealed that autocrine IFN-α/β upregulated TRAIL expression on activated T cells to elicit MDSC apoptosis via the TRAIL–DR5 interaction and acted synergistically with TNF-α to inhibit MDSC function of suppressing the T-cell response through the JNK-NMDAR-ARG-1 pathway. Moreover, blockade of IFN-α/β and TNF-α abolished the therapeutic efficacy of anti-PD-1 treatment by preserving the frequency and suppressive activity of infiltrating MDSCs in a CRC mouse model. This result suggested that reprogramming MDSCs by IFN-α/β and TNF-α from activated T cells was necessary for successful anti-PD-1 treatment and might serve as a novel strategy to improve the response and efficacy of anticancer therapy. Nature Publishing Group UK 2021-01-08 /pmc/articles/PMC7791142/ /pubmed/33414378 http://dx.doi.org/10.1038/s41392-020-00377-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chen, Jing
Sun, Hong-Wei
Yang, Yan-Yan
Chen, Hai-Tian
Yu, Xing-Juan
Wu, Wen-Chao
Xu, Yi-Tuo
Jin, Li-Lian
Wu, Xiao-Jun
Xu, Jing
Zheng, Limin
Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer
title Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer
title_full Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer
title_fullStr Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer
title_full_unstemmed Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer
title_short Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer
title_sort reprogramming immunosuppressive myeloid cells by activated t cells promotes the response to anti-pd-1 therapy in colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791142/
https://www.ncbi.nlm.nih.gov/pubmed/33414378
http://dx.doi.org/10.1038/s41392-020-00377-3
work_keys_str_mv AT chenjing reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT sunhongwei reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT yangyanyan reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT chenhaitian reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT yuxingjuan reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT wuwenchao reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT xuyituo reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT jinlilian reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT wuxiaojun reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT xujing reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer
AT zhenglimin reprogrammingimmunosuppressivemyeloidcellsbyactivatedtcellspromotestheresponsetoantipd1therapyincolorectalcancer