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 BosenbergZhang 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

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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 languageEnglish
Article numbere2025840118
Number of pages12
JournalProceedings of the National Academy of Sciences
Volume118
Issue number8
Early online date18 Feb 2021
DOIs
Publication statusPublished - 23 Feb 2021

Keywords

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

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