Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation

Yixuan Zhou; Ingmar Niels Bastian; Mark D. Long; Michelle Dow; Weihua Li; Rachael Katie Ngu; Laura Antonucci; Jian Yu Huang; Qui T. Phung; Xi-he Zhao; Sourav Banerjee; Xue-Jia Lin; Hongxia Wang; Brian Dang; Sylvia Choi; Daniel Karin; Hua Su; Mark H. Ellisman; Christina Jamieson; Marcus Bosenberg; Zhang Cheng; Johannes Haybaeck; Lukas Kenner; Kathleen M. Fisch; Richard Bourgon; Genevive Hernandez; Jennie R. Lill; Song Liu; Hannah Carter; Ira Mellman; Michael Karin; Shabnam Shalapour

doi:10.1073/pnas.2025840118

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation

Yixuan Zhou
, Ingmar Niels Bastian
, Mark D. Long
, Michelle Dow
, Weihua Li
, Rachael Katie Ngu
, Laura Antonucci
, Jian Yu Huang
, Qui T. Phung
, Xi-he Zhao
, Sourav Banerjee
, Xue-Jia Lin
, Hongxia Wang
, Brian Dang
, Sylvia Choi
, Daniel Karin
, Hua Su
, Mark H. Ellisman
, Christina Jamieson
, Marcus Bosenberg

Zhang Cheng, Johannes Haybaeck, Lukas Kenner, Kathleen M. Fisch, Richard Bourgon, Genevive Hernandez, Jennie R. Lill, Song Liu, Hannah Carter, Ira Mellman, Michael Karin (Lead / Corresponding author), Shabnam Shalapour (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

94 Citations (Scopus)

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Abstract

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I–dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I–expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had “epigenetically down-regulated,” but had not permanently lost MHC-I AgPP activity.

Original language	English
Article number	e2025840118
Number of pages	12
Journal	Proceedings of the National Academy of Sciences
Volume	118
Issue number	8
Early online date	18 Feb 2021
DOIs	https://doi.org/10.1073/pnas.2025840118
Publication status	Published - 23 Feb 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

histone acetylation
NF-kB
MHC-I
antigen presentation
immune checkpoint inhibitors
Antigen presentation
NF-κB
Histone acetylation
Immune checkpoint inhibitors

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.2025840118Licence: CC BY

Author Accepted ManuscriptAccepted author manuscript, 3.83 MB
Final published versionFinal published version, 3.87 MBLicence: CC BY

Cite this

Zhou, Y., Bastian, I. N., Long, M. D., Dow, M., Li, W., Ngu, R. K., Antonucci, L., Huang, J. Y., Phung, Q. T., Zhao, X., Banerjee, S., Lin, X.-J., Wang, H., Dang, B., Choi, S., Karin, D., Su, H., Ellisman, M. H., Jamieson, C., ... Shalapour, S. (2021). Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation. Proceedings of the National Academy of Sciences, 118(8), Article e2025840118. https://doi.org/10.1073/pnas.2025840118

@article{4fae99c24eed4eed90f5eef16f3e25c4,

title = "Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation",

abstract = "Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I{\textendash}dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I{\textendash}expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had {\textquotedblleft}epigenetically down-regulated,{\textquotedblright} but had not permanently lost MHC-I AgPP activity.",

keywords = "histone acetylation, NF-kB, MHC-I, antigen presentation, immune checkpoint inhibitors, Antigen presentation, NF-κB, Histone acetylation, Immune checkpoint inhibitors",

author = "Yixuan Zhou and Bastian, \{Ingmar Niels\} and Long, \{Mark D.\} and Michelle Dow and Weihua Li and Ngu, \{Rachael Katie\} and Laura Antonucci and Huang, \{Jian Yu\} and Phung, \{Qui T.\} and Xi-he Zhao and Sourav Banerjee and Xue-Jia Lin and Hongxia Wang and Brian Dang and Sylvia Choi and Daniel Karin and Hua Su and Ellisman, \{Mark H.\} and Christina Jamieson and Marcus Bosenberg and Zhang Cheng and Johannes Haybaeck and Lukas Kenner and Fisch, \{Kathleen M.\} and Richard Bourgon and Genevive Hernandez and Lill, \{Jennie R.\} and Song Liu and Hannah Carter and Ira Mellman and Michael Karin and Shabnam Shalapour",

year = "2021",

month = feb,

day = "23",

doi = "10.1073/pnas.2025840118",

language = "English",

volume = "118",

journal = "Proceedings of the National Academy of Sciences",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "8",

}

Zhou, Y, Bastian, IN, Long, MD, Dow, M, Li, W, Ngu, RK, Antonucci, L, Huang, JY, Phung, QT, Zhao, X, Banerjee, S, Lin, X-J, Wang, H, Dang, B, Choi, S, Karin, D, Su, H, Ellisman, MH, Jamieson, C, Bosenberg, M, Cheng, Z, Haybaeck, J, Kenner, L, Fisch, KM, Bourgon, R, Hernandez, G, Lill, JR, Liu, S, Carter, H, Mellman, I, Karin, M & Shalapour, S 2021, 'Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation', Proceedings of the National Academy of Sciences, vol. 118, no. 8, e2025840118. https://doi.org/10.1073/pnas.2025840118

TY - JOUR

T1 - Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation

AU - Zhou, Yixuan

AU - Bastian, Ingmar Niels

AU - Long, Mark D.

AU - Dow, Michelle

AU - Li, Weihua

AU - Ngu, Rachael Katie

AU - Antonucci, Laura

AU - Huang, Jian Yu

AU - Phung, Qui T.

AU - Zhao, Xi-he

AU - Banerjee, Sourav

AU - Lin, Xue-Jia

AU - Wang, Hongxia

AU - Dang, Brian

AU - Choi, Sylvia

AU - Karin, Daniel

AU - Su, Hua

AU - Ellisman, Mark H.

AU - Jamieson, Christina

AU - Bosenberg, Marcus

AU - Cheng, Zhang

AU - Haybaeck, Johannes

AU - Kenner, Lukas

AU - Fisch, Kathleen M.

AU - Bourgon, Richard

AU - Hernandez, Genevive

AU - Lill, Jennie R.

AU - Liu, Song

AU - Carter, Hannah

AU - Mellman, Ira

AU - Karin, Michael

AU - Shalapour, Shabnam

PY - 2021/2/23

Y1 - 2021/2/23

N2 - Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I–dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I–expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had “epigenetically down-regulated,” but had not permanently lost MHC-I AgPP activity.

AB - Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I–dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I–expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had “epigenetically down-regulated,” but had not permanently lost MHC-I AgPP activity.

KW - histone acetylation

KW - NF-kB

KW - MHC-I

KW - antigen presentation

KW - immune checkpoint inhibitors

KW - Antigen presentation

KW - NF-κB

KW - Histone acetylation

KW - Immune checkpoint inhibitors

U2 - 10.1073/pnas.2025840118

DO - 10.1073/pnas.2025840118

M3 - Article

C2 - 33602823

SN - 0027-8424

VL - 118

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

IS - 8

M1 - e2025840118

ER -

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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