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

  • Zhou, Yixuan
  • Bastian, Ingmar Niels
  • Long, Mark D
  • Dow, Michelle
  • Li, Weihua
  • Liu, Tao
  • Ngu, Rachael Katie
  • Antonucci, Laura
  • Huang, Jian Yu
  • Phung, Qui T
  • Zhao, Xi-He
  • Banerjee, Sourav
  • Lin, Xue-Jia
  • Wang, Hongxia
  • Dang, Brian
  • Choi, Sylvia
  • Karin, Daniel
  • Su, Hua
  • Ellisman, Mark H
  • Jamieson, Christina
  • And 13 more
Publication Date
Feb 01, 2021
eScholarship - University of California
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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.

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