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CARM1 Inhibition Enhances Cytotoxic T-cell Function and Sensitizes Resistant Cancers to Immune Attack

ABSTRACT: Several cancer drugs activate innate immune pathways in tumor cells but unfortunately compromise anti-tumor immune function. We discovered that inhibition of Carm1, an epigenetic enzyme, elicited beneficial effects in both cytotoxic T cells and tumor cells. Carm1 inactivation in cytotoxic T cells enhanced their activation state and anti-tumor function. In contrast, Carm1 inhibition in tumor cells resulted in genomic damage and activation of the cGAS-STING pathway. Inactivation of Med12, a regulatory component of the Mediator complex, elicited the same tumor cell phenotype, thereby connecting Carm1 to regulation of transcription. Inhibition of Carm1 induced potent T cell mediated tumor immunity and sensitized resistant, highly aggressive tumor cells to checkpoint blockade. The Carm1 – Med12 pathway thus offers an opportunity to enhance anti-tumor immunity while simultaneously sensitizing resistant tumor cells to immune attack.

ORGANISM(S): Mus musculus

PROVIDER: GSE144917 | GEO | 2022/01/31

REPOSITORIES: GEO

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CARM1 Methylates MED12 to Regulate its RNA Binding Ability

Project description:The coactivator-associated arginine methyltransferase (CARM1) functions as a regulator for transcription, splicing and chromatin regulation by methylating a diverse array of substrates. In this study, we used CARM1 substrate antibodies to perform immunoprecipitation coupled with mass spectrometry (IP-MS) in MEFs and identified Mediator Subunit 12 (MED12) as a novel substrate for CARM1. ChIP-seq analysis using CARM1, MED12 and H3R17me2a (represents ‘CARM1 activity’) antibodies revealed that MED12 targeted by CARM1 is recruited to the EREs (estrogen-responsive elements). Additionally, RT-PCR studies showed that the MED12R1899K mutation disrupting the methylation site reduced the expression of ER-target genes. Thus, MED12 methylation targets it to ER-specific enhancers and positively modulates transcription of Estrogen-driven genes.

2018-09-05 | GSE72848 | GEO

CARM1 Inhibition Enhances Cytotoxic T-cell Function and Sensitizes Resistant Cancers to Immune Attack

Project description:CARM1 Inhibition Enhances Cytotoxic T-cell Function and Sensitizes Resistant Cancers to Immune Attack

| PRJNA605329 | ENA

High-dose Ascorbic acid synergizes with anti-PD1 in a Lymphoma mouse model

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2020-01-27 | GSE141444 | GEO

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

2020-01-27 | GSE141397 | GEO

Wilson2012 - tumor vaccine efficacy

Project description:The paper describes a model of antitumor vaccine therapy. Created by COPASI 4.25 (Build 207) This model is described in the article: A Mathematical Model of the Enhancement of Tumor Vaccine Efficacy by Immunotherapy Shelby Wilson and Doron Levy Bull Math Biol. 2012 July ; 74(7) Abstract: TGF-β is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-β inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-β and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-β concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-β treatment, vaccine treatment, and combined anti-TGF-β vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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PI3Kβ controls immune evasion in PTEN-deficient breast tumors

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2023-03-07 | GSE225064 | GEO

Rhodes2019 - Immune-Mediated theory of Metastasis

Project description:Abstract: Accumulating experimental and clinical evidence suggest that the immune response to cancer is not exclusively anti-tumor. Indeed, the pro-tumor roles of the immune system - as suppliers of growth and pro-angiogenic factors or defenses against cytotoxic immune attacks, for example - have been long appreciated, but relatively few theoretical works have considered their effects. Inspired by the recently proposed "immune-mediated" theory of metastasis, we develop a mathematical model for tumor-immune interactions at two anatomically distant sites, which includes both anti- and pro-tumor immune effects, and the experimentally observed tumor-induced phenotypic plasticity of immune cells (tumor "education" of the immune cells). Upon confrontation of our model to experimental data, we use it to evaluate the implications of the immune-mediated theory of metastasis. We find that tumor education of immune cells may explain the relatively poor performance of immunotherapies, and that many metastatic phenomena, including metastatic blow-up, dormancy, and metastasis to sites of injury, can be explained by the immune-mediated theory of metastasis. Our results suggest that further work is warranted to fully elucidate the pro-tumor effects of the immune system in metastatic cancer.

2020-03-28 | BIOMD0000000926 | BioModels

Inactivation of interferon signaling promotes the establishment of an immunosuppressive microenvironment in colorectal cancers

Project description:Tumors arise and grow despite anti-cancer immune responses. These responses can be stimulated by immunotherapies such as immune checkpoint inhibitors (e.g. anti-PD1 antibodies) and chimeric antigen receptors (CAR). Efficacy of these agents in solid tumors including colorectal cancers (CRC) is limited by immunosuppressive tumor microenvironment (TME) that prevents killing of malignant cells by cytotoxic T lymphocytes (CTL). Understanding the nature of TME-generated immunosuppression is of paramount importance. Here we report that TME elicited immunosuppression via eliminating activated CTL; this elimination required TME stress-induced downregulation of the IFNAR1 chain of type I interferon (IFN) receptor and attenuation of its signaling. Downregulation of IFNAR1 was observed in human colorectal cancers (CRC) and in mouse CRC models where it was required for efficient tumor development and progression. Stabilization of IFNAR1 on CTL improved their survival and increased anti- tumor activities of CAR T cells and PD1 inhibitors thereby providing a rationale for targeting IFNAR1 degradation for immunotherapies optimization. Two genotypes of mice were examined either 9 or 21 days post injection of MC38 colon cancer cells or MC38mRFP cells, respectively. 2-3 replicate mice were analyzed on separate arrays for each condition. 6 conditions in total were analyzed.

2016-01-15 | E-GEOD-76889 | biostudies-arrayexpress

Boer1985 - Macrophage T cell interaction in anti-tumor response

Project description:In this paper we present a model of the macrophage T lymphocyte interactions that generate an anti-tumor immune response. The modseple cifies i) induction of cytotoxic T lymphocytes, ii) antigen presentation by macrophages, which leads to iii) activation of helper T cells, and iv) production of lymphoid factors, which induce a) cytotoxic macrophages, b) T lymphocyte proliferation, and c) an inflammation reaction. Tumor escape mechanisms (suppression, antigenic heterogeneity) have been deliberately omitted from the model.

2019-11-13 | MODEL1911130003 | BioModels

mNET sequencing facilitates identification of native elongating transcripts in control and Carm1 KO melanoma cells

Project description:We investigated whether RNA Pol II mediated transcription was altered in Carm1 KO compared to control KO tumor cells. We examined p-Ser2 CTD Pol II relative to total CTD Pol II using mammalian native elongating transcript sequencing (mNET-Seq) (Nojima et al., 2016). Inactivation of the Carm1 gene substantially increased the normalized read density of p-Ser2 CTD Pol II tags relative total Pol II tags. These data provide evidence for altered transcriptional regulation in Carm1 deficient cells.

2022-01-31 | GSE148905 | GEO

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