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Selected Publication:

Type of publication: Journal Article
Type of document: Full Paper

Year: 2021

Authors: Zhou, Y; Bastian, IN; Long, MD; Dow, M; Li, W; Liu, T; Ngu, RK; Antonucci, L; Huang, JY; Phung, QT; Zhao, XH; Banerjee, S; Lin, XJ; 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

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

Source: Proc Natl Acad Sci U S A. 2021; 118(8):e2025840118



Authors Vetmeduni Vienna:

Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals


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.


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