Tumor Cell–Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer

Abstract

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.

Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer

“…It has become increasingly clear that tumor cells play a central role in establishing a permissive immune TME by releasing secreted factors that can actively drive the exclusion of T cells and resistance to immunotherapy (7)(8)(9). Although several cancer cell-intrinsic pathways have been reported to influence the composition of the immune TME (10)(11)(12)(13)(14)(15)(16)(17)(18)(19), the key genetic and epigenetic drivers of this process remain largely unknown.…”

“…T cell-inflamed and non-T cell-inflamed tumors derived from our panel of PDA tumor cell clones exhibit heterogeneous responses to a combination immunotherapy regimen consisting of gemcitabine (G), abraxane (A), CD40 agonistic antibody (F), CTLA4-blocking antibody (C), and PD-1-blocking antibody (P), hereafter referred to as GAFCP (10)(11)(12). GAFCP therapy improves clinical outcomes in preclinical mouse models of PDA (31,32), and a similar regimen has shown promising results and is currently being tested in a phase II clinical trial of patients with metastatic PDA (NCT03214250; ref.…”

Prognostic values and immune suppression of the S100A family in pancreatic cancer

“…Immune therapy has been a landmark improvement over the last decade for the treatment of various cancers, such as melanoma, non–small‐cell lung cancer and hepatocellular carcinoma 3‐8 . However, these immune checkpoint inhibitors have limited effectivities for PC as single agents, due to the limited infiltration and impaired anti‐tumour effect of CD8 + T cells in the TME of PC 9‐11 . Consequently, the identification of reliable prognostic biomarkers and drug targets involved in the tumorigenesis and immunosuppression of PC is crucial for developing more useful immunotherapeutic drugs for PC patients.…”

Noncoding RNAs Associated with Therapeutic Resistance in Pancreatic Cancer

“…Ubiquitin-specific-processing protease 22 ( USP22 ) has been recognized to promote EMT process and metastasis via activating FAK and repressing anti-cancer immunity in PaC [ 184 , 185 ]. USP22 also increases LC3II and autophagosome levels so that USP22 can enhance gemcitabine resistance through activating autophagy [ 186 ].…”