@article{709fda5cac01494fa4e9efbf4aa802e5,
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–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.",
keywords = "Antigen presentation, Histone acetylation, Immune checkpoint inhibitors, MHC-I, NF-κB",
author = "Yixuan Zhou and Bastian, {Ingmar Niels} and Long, {Mark D.} and Michelle Dow and Weihua Li and Tao Liu and Ngu, {Rachael Katie} and Laura Antonucci and Huang, {Jian Yu} and Phung, {Qui T.} and Zhao, {Xi He} and Sourav Banerjee and Lin, {Xue Jia} 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",
note = "Funding Information: ACKNOWLEDGMENTS. We thank N. T. Ryujin, A. Perkins, C. R. Lichtenstern, T. Deerinck, M. Mackey, D. T. Tam, S. Lee, E. Sanchez-Lopez, S. Pandit, K. Wong, and M. Muldong for technical support and help; and A. Birmingham, L. Delamarre, E. Fokas, and C. M. R{\"o}del for discussions and advice. S.S. was supported by Prostate Cancer Foundation Young Investigator Award, Merck Investigator Studies Program 57917, and the National Institute on Alcohol Abuse and Alcoholism funded Southern California Research Center for Alcoholic Liver and Pancreatic Diseases & Cirrhosis (P50 AA011999). Work in the M.K. laboratory was supported by grants from the NIH (AI043477, CA128814, and CA211794), the Tower Cancer Research Foundation, San Diego National Cancer Institute{\textquoteright}s Cancer Centers Council (C3), and Padres Pedal the Cause No. PTC2018. Additional support came from U01AA027681 (to S.S. and M.K.), P01 CA128814 (to M.K./Ze{\textquoteright}ev Ronai [Cancer Center, Sanford Funding Information: K.M.F.), NIH P41GM103412, R24GM137200, and S10OD021784 (to M.H.E.), Mary Kay Ash Breast Cancer Grant 047.16, and Moore Cancer Center award (to S.B. and J. E. Dixon [Department of Pharmacology, University of California San Diego]). Funding Information: Burnham Prebys Medical Discovery Institute] and M.B.), U24CA232979 (to S.L.), DP5‐OD017937 (to H.C.), 111 project (B16021) (to X.-J.L.), NIH National Library of Medicine Training Grant T15LM011271 (to M.D.), NIH Grant UL1TR001442 of Clinical and Translational Science Awards (to Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = feb,
day = "23",
doi = "10.1073/pnas.2025840118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "8",
}