Acquired resistance during adoptive cell therapy by transcriptional silencing of immunogenic antigens

Ben Wylie, Jonathan Chee, Catherine A. Forbes, Mitchell Booth, Shane R. Stone, Anthony Buzzai, Ana Abad, Bree Foley, Mark N. Cruickshank, Jason Waithman

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Immunotherapies such as adoptive cell therapy (ACT) are promising treatments for solid cancers. However, relapsing disease remains a problem and the molecular mechanisms underlying resistance are poorly defined. We postulated that the deregulated epigenetic landscape in cancer cells could underpin the acquisition of resistance to immunotherapy. To address this question, two preclinical models of ACT were employed to study transcriptional and epigenetic regulatory processes within ACT-treated cancer cells. In these models ACT consistently causes robust tumor regression, but resistance develops and tumors relapse. We identified down-regulated expression of immunogenic antigens at the mRNA level correlated with escape from immune control. To determine whether this down-regulation was under epigenetic control, we treated escaped tumor cells with DNA demethylating agents, azacytidine (AZA) and decitabine (DEC). AZA or DEC treatment restored antigen expression in a proportion of the tumor population. To explore the importance of other epigenetic modifications we isolated tumor cells refractory to DNA demethylation and screened clones against a panel of 19 different epigenetic modifying agents (EMAs). The library of EMAs included inhibitors of a range of chromosomal and transcription regulatory protein complexes, however, when tested as single agents none restored further antigen expression. These findings suggest that tumor cells employ multiple epigenetic and genetic mechanisms to evade immune control, and a combinatorial approach employing several EMAs targeting transcription and genome stability may be required to overcome tumor resistance to immunotherapy.

Original languageEnglish
Number of pages11
JournalOncoImmunology
DOIs
Publication statusE-pub ahead of print - 31 May 2019

Cite this

@article{6629b25986f7447691a0dc12cb4402c0,
title = "Acquired resistance during adoptive cell therapy by transcriptional silencing of immunogenic antigens",
abstract = "Immunotherapies such as adoptive cell therapy (ACT) are promising treatments for solid cancers. However, relapsing disease remains a problem and the molecular mechanisms underlying resistance are poorly defined. We postulated that the deregulated epigenetic landscape in cancer cells could underpin the acquisition of resistance to immunotherapy. To address this question, two preclinical models of ACT were employed to study transcriptional and epigenetic regulatory processes within ACT-treated cancer cells. In these models ACT consistently causes robust tumor regression, but resistance develops and tumors relapse. We identified down-regulated expression of immunogenic antigens at the mRNA level correlated with escape from immune control. To determine whether this down-regulation was under epigenetic control, we treated escaped tumor cells with DNA demethylating agents, azacytidine (AZA) and decitabine (DEC). AZA or DEC treatment restored antigen expression in a proportion of the tumor population. To explore the importance of other epigenetic modifications we isolated tumor cells refractory to DNA demethylation and screened clones against a panel of 19 different epigenetic modifying agents (EMAs). The library of EMAs included inhibitors of a range of chromosomal and transcription regulatory protein complexes, however, when tested as single agents none restored further antigen expression. These findings suggest that tumor cells employ multiple epigenetic and genetic mechanisms to evade immune control, and a combinatorial approach employing several EMAs targeting transcription and genome stability may be required to overcome tumor resistance to immunotherapy.",
keywords = "Cancer, immunotherapy, adoptive cell therapy, acquired resistance, epigenetic modifiers, immunoediting, transcriptional silencing, MHC CLASS-I, TUMOR-INFILTRATING LYMPHOCYTES, METASTATIC MELANOMA, DNA METHYLATION, EPIGENETIC REGULATION, PROMOTER METHYLATION, IMMUNE EVASION, CANCER-CELLS, IFN-GAMMA, IMMUNOTHERAPY",
author = "Ben Wylie and Jonathan Chee and Forbes, {Catherine A.} and Mitchell Booth and Stone, {Shane R.} and Anthony Buzzai and Ana Abad and Bree Foley and Cruickshank, {Mark N.} and Jason Waithman",
year = "2019",
month = "5",
day = "31",
doi = "10.1080/2162402X.2019.1609874",
language = "English",
journal = "Oncolmmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",

}

Acquired resistance during adoptive cell therapy by transcriptional silencing of immunogenic antigens. / Wylie, Ben; Chee, Jonathan; Forbes, Catherine A.; Booth, Mitchell; Stone, Shane R.; Buzzai, Anthony; Abad, Ana; Foley, Bree; Cruickshank, Mark N.; Waithman, Jason.

In: OncoImmunology, 31.05.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Acquired resistance during adoptive cell therapy by transcriptional silencing of immunogenic antigens

AU - Wylie, Ben

AU - Chee, Jonathan

AU - Forbes, Catherine A.

AU - Booth, Mitchell

AU - Stone, Shane R.

AU - Buzzai, Anthony

AU - Abad, Ana

AU - Foley, Bree

AU - Cruickshank, Mark N.

AU - Waithman, Jason

PY - 2019/5/31

Y1 - 2019/5/31

N2 - Immunotherapies such as adoptive cell therapy (ACT) are promising treatments for solid cancers. However, relapsing disease remains a problem and the molecular mechanisms underlying resistance are poorly defined. We postulated that the deregulated epigenetic landscape in cancer cells could underpin the acquisition of resistance to immunotherapy. To address this question, two preclinical models of ACT were employed to study transcriptional and epigenetic regulatory processes within ACT-treated cancer cells. In these models ACT consistently causes robust tumor regression, but resistance develops and tumors relapse. We identified down-regulated expression of immunogenic antigens at the mRNA level correlated with escape from immune control. To determine whether this down-regulation was under epigenetic control, we treated escaped tumor cells with DNA demethylating agents, azacytidine (AZA) and decitabine (DEC). AZA or DEC treatment restored antigen expression in a proportion of the tumor population. To explore the importance of other epigenetic modifications we isolated tumor cells refractory to DNA demethylation and screened clones against a panel of 19 different epigenetic modifying agents (EMAs). The library of EMAs included inhibitors of a range of chromosomal and transcription regulatory protein complexes, however, when tested as single agents none restored further antigen expression. These findings suggest that tumor cells employ multiple epigenetic and genetic mechanisms to evade immune control, and a combinatorial approach employing several EMAs targeting transcription and genome stability may be required to overcome tumor resistance to immunotherapy.

AB - Immunotherapies such as adoptive cell therapy (ACT) are promising treatments for solid cancers. However, relapsing disease remains a problem and the molecular mechanisms underlying resistance are poorly defined. We postulated that the deregulated epigenetic landscape in cancer cells could underpin the acquisition of resistance to immunotherapy. To address this question, two preclinical models of ACT were employed to study transcriptional and epigenetic regulatory processes within ACT-treated cancer cells. In these models ACT consistently causes robust tumor regression, but resistance develops and tumors relapse. We identified down-regulated expression of immunogenic antigens at the mRNA level correlated with escape from immune control. To determine whether this down-regulation was under epigenetic control, we treated escaped tumor cells with DNA demethylating agents, azacytidine (AZA) and decitabine (DEC). AZA or DEC treatment restored antigen expression in a proportion of the tumor population. To explore the importance of other epigenetic modifications we isolated tumor cells refractory to DNA demethylation and screened clones against a panel of 19 different epigenetic modifying agents (EMAs). The library of EMAs included inhibitors of a range of chromosomal and transcription regulatory protein complexes, however, when tested as single agents none restored further antigen expression. These findings suggest that tumor cells employ multiple epigenetic and genetic mechanisms to evade immune control, and a combinatorial approach employing several EMAs targeting transcription and genome stability may be required to overcome tumor resistance to immunotherapy.

KW - Cancer

KW - immunotherapy

KW - adoptive cell therapy

KW - acquired resistance

KW - epigenetic modifiers

KW - immunoediting

KW - transcriptional silencing

KW - MHC CLASS-I

KW - TUMOR-INFILTRATING LYMPHOCYTES

KW - METASTATIC MELANOMA

KW - DNA METHYLATION

KW - EPIGENETIC REGULATION

KW - PROMOTER METHYLATION

KW - IMMUNE EVASION

KW - CANCER-CELLS

KW - IFN-GAMMA

KW - IMMUNOTHERAPY

U2 - 10.1080/2162402X.2019.1609874

DO - 10.1080/2162402X.2019.1609874

M3 - Article

JO - Oncolmmunology

JF - Oncolmmunology

SN - 2162-4011

ER -