Tumor Cell–Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer

Autor: Robert J. Norgard, Taiji Yamazoe, Salina Yuan, Fangxue Yan, Andres Blanco, Jinyang Li, Ben Z. Stanger
Rok vydání: 2020
Předmět:
0301 basic medicine
Cancer Research
Lung Neoplasms
Paclitaxel
medicine.medical_treatment
Immunology
Apoptosis
Deoxycytidine
Article
Gene Knockout Techniques
Interferon-gamma
Mice
03 medical and health sciences
Lymphocytes
Tumor-Infiltrating
0302 clinical medicine
Immune system
Pancreatic tumor
Albumins
Pancreatic cancer
Tumor Cells
Cultured
Tumor Microenvironment
medicine
Animals
Humans
Cytotoxic T cell
Cell Proliferation
Tumor microenvironment
business.industry
Myeloid-Derived Suppressor Cells
Immunotherapy
medicine.disease
Gemcitabine
Immune checkpoint
Killer Cells
Natural
Mice
Inbred C57BL
Pancreatic Neoplasms
030104 developmental biology
030220 oncology & carcinogenesis
Cancer cell
Cancer research
Female
business
Ubiquitin Thiolesterase
Carcinoma
Pancreatic Ductal
T-Lymphocytes
Cytotoxic
Zdroj: Cancer Immunol Res
ISSN: 2326-6074
2326-6066
Popis: 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.
Databáze: OpenAIRE
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