Tumor Cell-Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer.
Albumins
/ pharmacology
Animals
Apoptosis
/ drug effects
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Proliferation
/ drug effects
Deoxycytidine
/ analogs & derivatives
Female
Gene Knockout Techniques
Humans
Interferon-gamma
/ pharmacology
Killer Cells, Natural
/ drug effects
Lung Neoplasms
/ drug therapy
Lymphocytes, Tumor-Infiltrating
/ immunology
Mice
Mice, Inbred C57BL
Myeloid-Derived Suppressor Cells
/ immunology
Paclitaxel
/ pharmacology
Pancreatic Neoplasms
/ drug therapy
T-Lymphocytes, Cytotoxic
/ immunology
Tumor Cells, Cultured
Tumor Microenvironment
/ immunology
Ubiquitin Thiolesterase
/ genetics
Gemcitabine
Journal
Cancer immunology research
ISSN: 2326-6074
Titre abrégé: Cancer Immunol Res
Pays: United States
ID NLM: 101614637
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
28
08
2019
revised:
06
11
2019
accepted:
19
12
2019
pubmed:
25
12
2019
medline:
21
10
2020
entrez:
25
12
2019
Statut:
ppublish
Résumé
Although immune checkpoint blockade (ICB) improves clinical outcome in several types of malignancies, pancreatic ductal adenocarcinoma (PDA) remains refractory to this therapy. Preclinical studies have demonstrated that the relative abundance of suppressive myeloid cells versus cytotoxic T cells determines the efficacy of combination immunotherapies, which include ICB. Here, we evaluated the role of the ubiquitin-specific protease 22 (USP22) as a regulator of the immune tumor microenvironment (TME) in PDA. We report that deletion of USP22 in pancreatic tumor cells reduced the infiltration of myeloid cells and promoted the infiltration of T cells and natural killer (NK) cells, leading to an improved response to combination immunotherapy. We also showed that ablation of tumor cell-intrinsic USP22 suppressed metastasis of pancreatic tumor cells in a T-cell-dependent manner. Finally, we provide evidence that USP22 exerted its effects on the immune TME by reshaping the cancer cell transcriptome through its association with the deubiquitylase module of the SAGA/STAGA transcriptional coactivator complex. These results indicated that USP22 regulates immune infiltration and immunotherapy sensitivity in preclinical models of pancreatic cancer.
Identifiants
pubmed: 31871120
pii: 2326-6066.CIR-19-0661
doi: 10.1158/2326-6066.CIR-19-0661
pmc: PMC7173406
mid: NIHMS1547506
doi:
Substances chimiques
130-nm albumin-bound paclitaxel
0
Albumins
0
Deoxycytidine
0W860991D6
Interferon-gamma
82115-62-6
USP22 protein, mouse
EC 3.4.19.12
Ubiquitin Thiolesterase
EC 3.4.19.12
Paclitaxel
P88XT4IS4D
Gemcitabine
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
282-291Subventions
Organisme : NCI NIH HHS
ID : R01 CA229803
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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