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PABPC1L promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in renal cell carcinoma

ABSTRACT: The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241871 | GEO | 2024/02/14

REPOSITORIES: GEO

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PABPC1L promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in renal cell carcinoma [RIP-seq]

Project description:The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.

2024-02-14 | GSE255448 | GEO

Mitocans target tryptophan metabolism to remove the mimicry of tumour-initiating cells

Project description:Following therapy, tumour-initiating cells (TICs) survive and give rise to second-line tumours. Gene set enrichment analysis of microarray data and microRNA analysis confirmed the validity of spheroid cultures as models of TICs for breast and prostate cancer and mesothelioma cell lines. Pathway analysis revealed increased Trp metabolism in all types of TICs with indoleamine 2,3-dioxygenase (IDO) as the rate-limiting enzyme. TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. Mitocans, represented by vitamin E (VE) analogues, suppressed IDO1 in TICs with functional mitochondrial complex II, a target for the agents. IDO1 expression was regulated via a mechanism involving both transcriptional and post-transcriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work points to Trp metabolism as a novel mechanism of TICs to bypass the immune surveillance and to VE analogues as agents that remove this ‘mimicry’. Total RNA obtained from from breast cancer (MCF7), mesothelioma (IstMes2) and prostate cancer (LNCaP) adherent cell lines was compared to their corresponding sphere cultures

2013-11-01 | E-GEOD-41980 | biostudies-arrayexpress

SETD2 loss and ATR inhibition synergistically promote cGAS signaling and immunotherapy response in renal cell carcinoma

Project description:Immune checkpoint blockade (ICB) demonstrates durable clinical benefit only in a minority of renal cell carcinoma (RCC) patients. Identifying molecular features that determine response and developing approaches to enhance the response remain an urgent clinical need. Here we found that, in multiple RCC cell lines, targeting the ATR-CHK1 axis with pharmacological inhibitors increased cytosolic DNA accumulation, activated the cGAS-IRF3-dependent cytosolic DNA sensing pathway, and resulted in the inflammatory cytokine expression. SETD2 mutated RCC cell lines or tumor samples were associated with preferential ATR-CHK1 activation over ATM-CHK2 activation. SETD2 knockdown promoted the cytosolic DNA sensing pathway and conferred greater sensitivity in response to ATR-CHK1 inhibition. In murine Renca tumors, Setd2 knockdown and ATR inhibitor VE822 synergistically promoted cytosolic DNA sensing pathway, immune cell infiltration, and immune checkpoint protein expression. Setd2 deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or in combination with VE822 than Setd2 proficient tumors. SETD2 mutations were associated with a higher response rate and prolonged overall survival in ICB-treated RCC patients, but not in non-ICB-treated RCC patients. This study provides a mechanism-based guidance to develop more personalized combination therapy regimens for RCC patients with SETD2 mutations.

2023-07-25 | GSE234732 | GEO

Tumor endothelial up-regulation of IDO1 limits the response to CD40-stimulating immunotherapy

Project description:CD40-stimulating immunotherapy elicits potent anti-tumor responses, which are mainly T-cell dependent. Here, we have investigated how tumor endothelial cells respond to CD40-stimulating immunotherapy by isolating endothelial cells from B16.F10 melanoma in anti-CD40 treated or isotype treated mice followed by RNA-sequencing. Gene set enrichment analysis revealed an increase in interferon- related responses in tumor endothelial cells following anti-CD40 therapy. The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) was preferentially expressed in endothelial cells, and it was up-regulated upon anti-CD40 treatment. IDO1 expression in tumor endothelium was positively correlated to T-cell infiltration and to increased expression of IFNγ in the tumor microenvironment. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic anti-CD40 therapy with the IDO1 inhibitor epacadostat delayed tumor growth and increased survival in B16.F10 tumor-bearing mice, which was associated with increased activation of tumor-infiltrating T-cells. Hereby, we have uncovered an immunosuppressive feedback mechanism, in which tumor vessels limit the efficacy of cancer immunotherapy by up-regulating IDO1 in response to T-cell activation.

2020-04-06 | GSE130679 | GEO

An adverse tumor-protective effect of IDO1 inhibition

Project description:Indoleamine 2, 3-dioxygenase 1 (IDO1) is a metabolic enzyme catalyzing the conversion of the essential amino acid tryptophan to kynurenine. It is induced by IFNg and its expression is linked to poor prognosis across various cancer types. T cells are particularly sensitive to IDO1-dependent tryptophan deprivation in the tumor microenvironment, leading to tumor immune resistance. Therefore, IDO1 inhibitors, such as epacadostat, have been developed, aiming to restore T cell antitumor activity. However, a recent phase III trial assessing the clinical benefit of epacadostat with the PD-1 antibody pembrolizumab in melanoma failed. This prompted us to study the role of IDO1, and the effect of its inhibition, on tumor cells that are under IFNg treatment and T cell attack. We showed that IDO1-mediated tryptophan depletion contributes to the anti-tumor effect of CD8 T cells. Thus, while epacadostat expectedly replenished tryptophan -the desired effect-, this led to adverse protection of melanoma cells from T cell-derived IFNg. RNA sequencing and ribosome profiling of (patient-derived) melanoma cell lines revealed that IFNg caused general protein translation shut down, which was reversed by IDO1 inhibition. Impaired translation was accompanied by an amino acid deprivation-dependent stress response driving ATF4high and MITFlow transcriptomic signatures, which was also observed in melanoma patient tumors. Downregulation of MITF in tumors and PDX- derived cell lines upon treatment was strongly predictive of response to response, to checkpoint blockade-treatment and IFNg, respectively. Conversely, MITF restoration in cultured tumor cells caused T cell resistance. These results highlight the critical role of tryptophan in the melanoma response to T cell-derived IFNg, uncovering an unexpected negative consequence of IDO1 inhibition.

2023-01-16 | GSE198460 | GEO

Identification of indoleamine 2, 3-dioxygenase 1 (IDO1) regulated genes in human glioblastoma cell line U87

Project description:Transcriptome analysis of U87 cells under different treatments to identify IDO1-regulated genes Indoleamine 2, 3-dioxygenase 1 (IDO1) is a tryptophan (Trp) catabolic enzyme that converts Trp into downstream kynurinine (Kyn). Many studies have indicated that IDO1 is a critical suppressive immune checkpoint molecule invovled in various types of cancer. Canonically, the underlying mechanism of IDO1 immunosuppressive role is related with its enzyme activity, that is the depletion of Trp and accumulation of Kyn lead to increased tumor infiltrating suppressive regulatory T cells. Recent studies, however, challenged this hypothesis and imply that tumor cell-derived IDO1 can mediate immunosuppression independent of its enzyme activity. In this study, we aim to identify genes that are regulated by IDO1 in human glioblastoma cells, a gene expression regulatory function of IDO1 that is indepent of its enzyme activity.

2021-12-10 | GSE175700 | GEO

Mitocans target tryptophan metabolism to remove the mimicry of tumour-initiating cells

2013-11-01 | GSE41980 | GEO

USP14 Promotes Tryptophan Metabolism and Immune Suppression by Stabilizing IDO1 in Colorectal Cancer

Project description:IDO1 interacting proteins in two colorectal cancer cells and was subjected to beads, and the beads were washed by buffer and identified by mass spectrometry (MS)

2022-05-05 | PXD033718 | iProX

Analysis of HeLa cell transcriptome changes induced by IDO1-metabolism

Project description:We analyzed the mRNA changes iduced by treatment with IFNγ in the presence of the IDO1 inhibitors (indoximod, epacadostat and BMS986205) in wt and IDO1 ko HeLa cells.

2022-01-11 | GSE174116 | GEO

DNA Demethylation promotes ERV expression and activation of immune signaling in renal cell cancer cells

Project description:Recently, we reported that expression of endogenous retroviruses (ERVs), a class of transposable element, is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). Aberrant expression of ERVs can activate host antiviral responses, as well as produce neoantigens. ERV expression is repressed by DNA methylation and can be activated by DNA hypomethylating agents. Here, we investigate whether Decitabine, a DNA hypomethylating agent, can activate ERV expression and host antiviral defenses in RCC to potentially enhance response to ICB. Decitabine induced expression of ERV3-2 and ERV4700 in RCC cells lines, which was accompanied by activation of host antiviral defense genes and increased secretion of inflammatory cytokines. We validated this effect in primary human RCC cell lines. Knockout of RIG-I and MDA5 dsRNA sensors attenuated activation of antiviral responses associated with Decitabine treatment, and RIG-I and MDA5 immunoprecipitations showed increased ERV binding in RCC cells treated with Decitabine. Bioinformatic analysis of RNAseq data showed the Decitabine-induced gene signature could be associated with increased CD8 infiltration and response to ICB. Conditioned media from Decitabine treated RCC cells was capable of inducing host anti-viral defense in naïve RCC cells and could modestly improve activation of T-cells from healthy donors. Further, conditioned media from RCC cells treated with Decitabine significantly enhanced T-cell migration. In a small retrospective cohort of metastatic RCC patients treated with single-agent PD-1/PD-L1 blockade, activation of some host antiviral defense genes was significantly higher in responders compared with nonresponders. Thus, modulation of ERV expression by Decitabine to activate host antiviral defenses could represent a novel therapeutic strategy to enhance RCC patient response to immune checkpoint blockade.

2020-06-01 | GSE142381 | GEO

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