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The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity.

ABSTRACT: Although iron is required for cell proliferation, iron-dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron-mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron-responsive element-binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)-mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage-associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor-reactive T-cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.

SUBMITTER: Song J

PROVIDER: S-EPMC7857436 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity

Project description:Although iron is required for cell proliferation, iron-dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron-mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of Iron-responsive element-binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes Transferrin receptor protein 1 (TFRC)-mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, presence of OTUD1 promotes the release of damage associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor-reactive T cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.

| S-SCDT-EMBOR-2020-51162V1P | biostudies-other

The deubiquitinase OTUD1 attenuates periodontal inflammation by restricting neutrophil protein transport

Project description:We report that OTUD1 acts as an immune regulator in periodontitis. OTUD1 inhibits neutrophils migration to inflammatory site via blocking surface protein presentation. Our data reveals that activation of OTUD1 may be a potential strategy for periodontitis treatment.

2024-10-31 | GSE216573 | GEO

Inhibition of SIRPα in dendritic cells potentiates potent antitumor immunity.

Project description:Despite their central function in tumor immunity, dendritic cells (DCs) can respond to inhibitory signals and become tolerogenic, curtailing T cell responses in vivo. Here, we provide the evidence for an inhibitory function of signal regulatory protein (SIRP) α in DC survival and activation. In tumors from human liver cancer patients, infiltrative DCs expressed elevated levels of SIRPα, which is correlated with the induction of immune tolerance within the tumors. Silencing of SIRPα resulted in a significant increase in the longevity of antigen-pulsed DCs in the draining lymph nodes. In addition, SIRPα controls the activation and output of DCs. Silencing of DC-expressed SIRPα induced spontaneous and enhanced production of IL12 and costimulatory molecules, resulting in more potent cytotoxic T lymphocyte responses, including the eradication of previously established solid tumors. SIRPα exerted such effects, at least in part, via the association and sequestration of p85 subunit of PI3K. Thus, SIRPα is a critical regulator of DC lifespan and activity, and its inhibition might improve the clinical efficacy of DC-based tumor vaccines.

| S-EPMC5048764 | biostudies-literature

The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma.

Project description:Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large MM patient cohort (n = 4146), we observe no correlation between serum Ig levels and patient survival, while amount of intracellular Ig has a strong predictive effect. Focused CRISPR screen, transcriptional and proteomic analysis identify deubiquitinase OTUD1 as a critical mediator of Ig synthesis, proteasome inhibitor sensitivity and tumor burden in MM. Mechanistically, OTUD1 deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates Ig production which coincides with the accumulation of unfolded proteins and higher ER stress. The elevated load on proteasome ultimately potentiates myeloma response to proteasome inhibitors providing a window for a rational therapy. Collectively, our findings support the significance of the Ig production machinery as a biomarker and target in the combinatory treatment of MM patients.

| S-EPMC9649770 | biostudies-literature

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity.

Project description:Immune checkpoint blockade (ICB) therapies such as PD-1 antibodies have produced significant clinical responses in treating a variety of human malignancies, yet only a subset of cancer patients benefit from such therapy. To improve the ICB efficacy, combinations with additional therapeutics were under intensive investigation. Recently, special dietary compositions that can lower the cancer risk or inhibit cancer progression have drawn significant attention, although few were reported to show synergistic effects with ICB therapies. Interestingly, Fucoidan is naturally derived from edible brown algae and exhibits antitumor and immunomodulatory activities. Here we discover that fucoidan-supplemented diet significantly improves the antitumor activities of PD-1 antibodies in vivo. Specifically, fucoidan as a dietary ingredient strongly inhibits tumor growth when co-administrated with PD-1 antibodies, which effects can be further strengthened when fucoidan is applied before PD-1 treatments. Immune analysis revealed that fucoidan consistently promotes the activation of tumor-infiltrating CD8+ T cells, which support the evident synergies with ICB therapies. RNAseq analysis suggested that the JAK-STAT pathway is critical for fucoidan to enhance the effector function of CD8+ T cells, which could be otherwise attenuated by disruption of the T-cell receptor (TCR)/CD3 complex on the cell surface. Mechanistically, fucoidan interacts with this complex and augments TCR-mediated signaling that cooperate with the JAK-STAT pathway to stimulate T cell activation. Taken together, we demonstrated that fucoidan is a promising dietary supplement combined with ICB therapies to treat malignancies, and dissected an underappreciated mechanism for fucoidan-elicited immunomodulatory effects in cancer.

| S-EPMC8382313 | biostudies-literature

Local Depletion of Immune Checkpoint Ligand CTLA4 Expressing Cells in Tumor Beds Enhances Antitumor Host Immunity.

Project description:Near-infrared photoimmunotherapy (NIR-PIT) is a cancer treatment that utilizes antibody-photoabsorber (IR700) conjugates to selectively kill target cells by exposing them to NIR light. Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a major immune checkpoint ligand mediating antitumor immune suppression. Local depletion of CTLA4 expressing cells in the tumor bed with NIR-PIT could enhance antitumor immune responses by both blocking the CTLA4-axis and depleting immune suppressive cells. The aim of this study is to evaluate the antitumor efficacy of CTLA4-targeted NIR-PIT using four murine tumor models, MC38-luc, LL/2-luc, MOC2-luc, and MOC2. The CTLA4-targeted NIR-PIT depletes intratumoral CTLA4 expressing cells which are mostly regulatory T cells. In vivo CTLA4-targeted NIR-PIT yields complete responses in 80% of MC38-luc, 70% of LL/2-luc and 40% of MOC2-luc tumors prolonging survival in all cases. After CTLA4-targeted NIR-PIT, activation and infiltration of CD8+ T cells within the tumor microenvironment is observed. In conclusion, CTLA4-targeted NIR-PIT can effectively treat tumors by blocking the CTLA4-axis as well as by eliminating CTLA4-expressing immune suppressor cells, resulting in T cell mediated antitumor immunity. Local CTLA4-expressing cell depletion in tumor beds using NIR-PIT could be a promising new cancer immunotherapy for safely treating a variety of tumor types.

| S-EPMC8115697 | biostudies-literature

BPTF Depletion Enhances T-cell-Mediated Antitumor Immunity.

Project description:Genetic studies in fruit flies have implicated the chromatin remodeling complex nucleosome remodeling factor (NURF) in immunity, but it has yet to be studied in mammals. Here we show that its targeting in mice enhances antitumor immunity in two syngeneic models of cancer. NURF was disabled by silencing of bromodomain PHD-finger containing transcription factor (BPTF), the largest and essential subunit of NURF. We found that both CD8+ and CD4+ T cells were necessary for enhanced antitumor activity, with elevated numbers of activated CD8+ T cells observed in BPTF-deficient tumors. Enhanced cytolytic activity was observed for CD8+ T cells cocultured with BPTF-silenced cells. Similar effects were not produced with T-cell receptor transgenic CD8+ T cells, implicating the involvement of novel antigens. Accordingly, enhanced activity was observed for individual CD8+ T-cell clones from mice bearing BPTF-silenced tumors. Mechanistic investigations revealed that NURF directly regulated the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2 The PSMB8 inhibitor ONX-0914 reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor antigenicity and its depletion improves antigen processing, CD8 T-cell cytotoxicity, and antitumor immunity, identifying NURF as a candidate therapeutic target to enhance antitumor immunity. Cancer Res; 76(21); 6183-92. ©2016 AACR.

| S-EPMC5093041 | biostudies-literature

The deubiquitinase OTUD1 attenuates periodontal inflammation by restricting neutrophil protein transport

Project description:The deubiquitinase OTUD1 attenuates periodontal inflammation by restricting neutrophil protein transport

| PRJNA894293 | ENA

Gingyo-san enhances immunity and potentiates infectious bursal disease vaccination.

Project description:The purpose of the present study was to investigate the effects of Gingyo-san (GGS), a traditional Chinese medical formula, on peripheral lymphocyte proliferation and serum antibody titers in chickens vaccinated against the infectious bursal disease (IBD) virus. Treatment groups were fed one of three doses of GGS in their diet (0.5%, 1.0% and 2.0%, w/w), and the IBD vaccine was administered at 1 and 3 weeks of age. At Weeks 8, 12 and 16, changes in serum IBD antibody titers were measured via the micro-method and T cell proliferation. In gene expression experiments, GGS-treated peripheral T lymphocytes were stimulated with concanavalin A (ConA) for 24?h. The mRNA expression of interleukin-2 (IL-2), interferon-? (IFN-?), interleukin-4 (IL-4) and interleukin-12 (IL-12) was determined using a semi-quantitative RT-PCR assay. The results showed that a low dose of GGS could significantly raise the antibody titers. Medium and high doses of GGS enhanced IL-2 and IFN-? production. GGS altered the expression of IL-4 and IL-12 in T lymphocytes. CD4(+) T lymphocyte development was also skewed towards the Th1 phenotype. GGS enhanced cell-mediated immunity and augmented the effects of IBD vaccination in strengthening subsequent anti-viral responses.

| S-EPMC3095499 | biostudies-literature

C3d regulates immune checkpoint blockade and enhances antitumor immunity.

Project description:Despite expression of immunogenic polypeptides, tumors escape immune surveillance by engaging T cell checkpoint regulators and expanding Tregs, among other mechanisms. What orchestrates these controls is unknown. We report that free C3d, a fragment of the third component of complement, inside tumor cells - or associated with irradiated tumor cells and unattached to antigen - recruits, accelerates, and amplifies antitumor T cell responses, allowing immunity to reverse or even to prevent tumor growth. C3d enhances antitumor immunity independently of B cells, NK cells, or antibodies, but it does so by increasing tumor infiltrating CD8+ lymphocytes, by depleting Tregs, and by suppressing expression of programmed cell death protein 1 (PD-1) by T cells. These properties of C3d appear specific for the tumor and dependent on complement receptor 2, and they incur no obvious systemic toxicity. The heretofore unrecognized properties of free C3d suggest that protein might determine the effectiveness of immune surveillance and that increasing availability of the protein might prove advantageous in the treatment or prevention of cancer and premalignant conditions.

| S-EPMC5414554 | biostudies-literature

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