Tumor Cell-Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer

Cancer Immunol Res. 2020 Mar;8(3):282-291. doi: 10.1158/2326-6066.CIR-19-0661. Epub 2019 Dec 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / immunology*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Proliferation / drug effects
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Female
  • Gemcitabine
  • Gene Knockout Techniques
  • Humans
  • Interferon-gamma / pharmacology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Derived Suppressor Cells / immunology*
  • Paclitaxel / pharmacology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Cells, Cultured
  • Tumor Microenvironment / immunology
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / immunology*


  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Deoxycytidine
  • Interferon-gamma
  • USP22 protein, mouse
  • Ubiquitin Thiolesterase
  • Paclitaxel
  • Gemcitabine