Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment

Abstract The efficacy of immunotherapy is largely patient-specific due to heterogeneity in tumors. Combining statistic power from a variety of immunotherapies across cancer types, we found four biological pathways significantly correlated with patient survival following immunotherapy. The expression...

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Autores principales:	Naixue Yang, Fansen Ji, Liqing Cheng, Jingzhe Lu, Xiaofeng Sun, Xin Lin, Xun Lan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/d1b53626f5384d8199251343281d89a5
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spelling	oai:doaj.org-article:d1b53626f5384d8199251343281d89a52021-12-02T14:49:41ZKnockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment10.1038/s41698-021-00175-22397-768Xhttps://doaj.org/article/d1b53626f5384d8199251343281d89a52021-05-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00175-2https://doaj.org/toc/2397-768XAbstract The efficacy of immunotherapy is largely patient-specific due to heterogeneity in tumors. Combining statistic power from a variety of immunotherapies across cancer types, we found four biological pathways significantly correlated with patient survival following immunotherapy. The expression of immunotherapy prognostic marker genes (IPMGs) in these pathways can predict the patient survival with high accuracy not only in the TCGA cohort (89.36%) but also in two other independent cohorts (80.91%), highlighting that the activity of the IPMGs can reflect the sensitivity of the tumor immune microenvironment (TIME) to immunotherapies. Using mouse models, we show that knockout of one of the IPMGs, MALT1, which is critical for the T-cell receptor signaling, can eliminate the antitumor effect of anti-PD-1 treatment completely by impairing the activation of CD8+ T cells. Notably, knockout of another IPMG, CLEC4D, a C-type lectin receptor that expressed on myeloid cells, also reduced the effect of anti-PD-1 treatment potentially through maintaining the immunosuppressive effects of myeloid cells. Our results suggest that priming TIME via activating the IPMGs may increase the response rate and the effect of immune checkpoint blockers.Naixue YangFansen JiLiqing ChengJingzhe LuXiaofeng SunXin LinXun LanNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Naixue Yang Fansen Ji Liqing Cheng Jingzhe Lu Xiaofeng Sun Xin Lin Xun Lan Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment
description	Abstract The efficacy of immunotherapy is largely patient-specific due to heterogeneity in tumors. Combining statistic power from a variety of immunotherapies across cancer types, we found four biological pathways significantly correlated with patient survival following immunotherapy. The expression of immunotherapy prognostic marker genes (IPMGs) in these pathways can predict the patient survival with high accuracy not only in the TCGA cohort (89.36%) but also in two other independent cohorts (80.91%), highlighting that the activity of the IPMGs can reflect the sensitivity of the tumor immune microenvironment (TIME) to immunotherapies. Using mouse models, we show that knockout of one of the IPMGs, MALT1, which is critical for the T-cell receptor signaling, can eliminate the antitumor effect of anti-PD-1 treatment completely by impairing the activation of CD8+ T cells. Notably, knockout of another IPMG, CLEC4D, a C-type lectin receptor that expressed on myeloid cells, also reduced the effect of anti-PD-1 treatment potentially through maintaining the immunosuppressive effects of myeloid cells. Our results suggest that priming TIME via activating the IPMGs may increase the response rate and the effect of immune checkpoint blockers.
format	article
author	Naixue Yang Fansen Ji Liqing Cheng Jingzhe Lu Xiaofeng Sun Xin Lin Xun Lan
author_facet	Naixue Yang Fansen Ji Liqing Cheng Jingzhe Lu Xiaofeng Sun Xin Lin Xun Lan
author_sort	Naixue Yang
title	Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment
title_short	Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment
title_full	Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment
title_fullStr	Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment
title_full_unstemmed	Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment
title_sort	knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-pd-1 treatment
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d1b53626f5384d8199251343281d89a5
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Knockout of immunotherapy prognostic marker genes eliminates the effect of the anti-PD-1 treatment

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