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Cancer Res. 2019 Jun 10. pii: canres.3622.2018. doi: 10.1158/0008-5472.CAN-18-3622. [Epub ahead of print]

CBP/p300 drives the differentiation of Regulatory T cells through transcriptional and non-transcriptional mechanisms.

Author information

1
ES Biomarker Development, Genentech, Inc.
2
Department of Oncology Biomarker Development, Genentech, Inc.
3
Oncology Biomarker Development, Genentech, Inc.
4
Oncology Biomarker Development, Genentech.
5
Biomarkers/Translational science, IDEAYA Biosciences.
6
Genentech, Inc.
7
Pathology, Genentech, Inc.
8
Research, Genentech, Inc.
9
Bioinformatics, Q2 Solutions - EA Genomics.
10
Proteomics Service Group, Cell Signaling Technology Inc.
11
Hematology/Oncology, Children's Hospital of Los Angeles.
12
Discovery Oncology, Genentech Inc.
13
kite pharma.
14
Chemistry, Terns Pharmaceuticals.
15
Discovery Chemistry, Genentech, Inc.
16
Discovery and Early Development, Sanofi Oncology.
17
Kite Pharma.
18
Pathology, Genentech.
19
IDEAYA Biosciences zineb.mounir@mail.mcgill.ca.

Abstract

Regulatory T cells (Tregs) are immunosuppressive and negatively impact response to cancer immunotherapies. CREB-binding protein (CBP) and p300 are closely related acetyltransferases and transcriptional coactivators. Here, we evaluate the mechanisms by which CBP/p300 regulate Treg differentiation and the consequences of CBP/p300 loss-of-function mutations in follicular lymphoma. Transcriptional and epigenetic profiling identified a cascade of transcription factors essential for Treg differentiation. Mass spectrometry analysis showed that CBP/p300 acetylates prostacyclin synthase, which regulates Treg differentiation by altering pro-inflammatory cytokine secretion by T and B cells. Reduced Treg presence in tissues harboring CBP/p300 loss-of-function mutations was observed in follicular lymphoma. Our findings provide novel insights into the regulation of Treg differentiation by CBP/p300 with potential clinical implications on alteration of the immune landscape.

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