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 |
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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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