The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion

Chunwan Lu, Amy V. Paschall, Huidong Shi, Natasha Marie Savage, Jennifer L Waller, Maria Eugenia Sabbatini, Nicholas H. Oberlies, Cedric Pearce, Kebin Liu

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. Methods: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided. Results: PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03-.001) and when CTLs are neutralized (P = .03-<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, Inhibition of MLL1 in Combination with anti-PD-L1 or anti-PD-1 Antibody Immunotherapy Effectively Suppresses Pancreatic Tum. Growth in A FasL- and CTL-dependent Manner. Conclusions: the Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 Axis Play Contrasting Roles in Pancreatic Cancer Immune Survlnc. and Evasion. Targeting the MLL1-H3K4me3 Axis is An Effective Approach to Enhance the Efficacy of Checkpoint Immunotherapy Against Pancreatic Cancer.

Original languageEnglish (US)
Article numberdjw283
JournalJournal of the National Cancer Institute
Volume109
Issue number6
DOIs
StatePublished - Jan 1 2017

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Immune Evasion
Pancreatic Neoplasms
Cytotoxic T-Lymphocytes
Immunotherapy
Neoplasms
RNA Interference
Cell Line
Antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion. / Lu, Chunwan; Paschall, Amy V.; Shi, Huidong; Savage, Natasha Marie; Waller, Jennifer L; Sabbatini, Maria Eugenia; Oberlies, Nicholas H.; Pearce, Cedric; Liu, Kebin.

In: Journal of the National Cancer Institute, Vol. 109, No. 6, djw283, 01.01.2017.

Research output: Contribution to journalArticle

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abstract = "Background: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. Methods: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided. Results: PD-L1 is expressed in 60{\%} to 90{\%} of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2{\%} to 52.1{\%} of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03-.001) and when CTLs are neutralized (P = .03-<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, Inhibition of MLL1 in Combination with anti-PD-L1 or anti-PD-1 Antibody Immunotherapy Effectively Suppresses Pancreatic Tum. Growth in A FasL- and CTL-dependent Manner. Conclusions: the Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 Axis Play Contrasting Roles in Pancreatic Cancer Immune Survlnc. and Evasion. Targeting the MLL1-H3K4me3 Axis is An Effective Approach to Enhance the Efficacy of Checkpoint Immunotherapy Against Pancreatic Cancer.",
author = "Chunwan Lu and Paschall, {Amy V.} and Huidong Shi and Savage, {Natasha Marie} and Waller, {Jennifer L} and Sabbatini, {Maria Eugenia} and Oberlies, {Nicholas H.} and Cedric Pearce and Kebin Liu",
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AU - Shi, Huidong

AU - Savage, Natasha Marie

AU - Waller, Jennifer L

AU - Sabbatini, Maria Eugenia

AU - Oberlies, Nicholas H.

AU - Pearce, Cedric

AU - Liu, Kebin

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N2 - Background: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. Methods: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided. Results: PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03-.001) and when CTLs are neutralized (P = .03-<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, Inhibition of MLL1 in Combination with anti-PD-L1 or anti-PD-1 Antibody Immunotherapy Effectively Suppresses Pancreatic Tum. Growth in A FasL- and CTL-dependent Manner. Conclusions: the Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 Axis Play Contrasting Roles in Pancreatic Cancer Immune Survlnc. and Evasion. Targeting the MLL1-H3K4me3 Axis is An Effective Approach to Enhance the Efficacy of Checkpoint Immunotherapy Against Pancreatic Cancer.

AB - Background: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. Methods: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided. Results: PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03-.001) and when CTLs are neutralized (P = .03-<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, Inhibition of MLL1 in Combination with anti-PD-L1 or anti-PD-1 Antibody Immunotherapy Effectively Suppresses Pancreatic Tum. Growth in A FasL- and CTL-dependent Manner. Conclusions: the Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 Axis Play Contrasting Roles in Pancreatic Cancer Immune Survlnc. and Evasion. Targeting the MLL1-H3K4me3 Axis is An Effective Approach to Enhance the Efficacy of Checkpoint Immunotherapy Against Pancreatic Cancer.

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