RT Journal Article
SR Electronic
T1 Tumor Cell–Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 282
OP 291
DO 10.1158/2326-6066.CIR-19-0661
VO 8
IS 3
A1 Li, Jinyang
A1 Yuan, Salina
A1 Norgard, Robert J.
A1 Yan, Fangxue
A1 Yamazoe, Taiji
A1 Blanco, Andrés
A1 Stanger, Ben Z.
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/8/3/282.abstract
AB 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.