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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE76889 | GEO | 2016/01/15

SECONDARY ACCESSION(S): PRJNA308858

REPOSITORIES: GEO

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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

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2023-05-22 | GSE229054 | GEO

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Project description:Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and microsatellite stable (MSS) phenotypes. Although SHP2 is a potential target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts.

2022-01-01 | GSE164908 | GEO

Inhibition of PARP11 inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.

Project description:Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenviroment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here we demonstrate that Poly-(ADP-ribose)-polymerase-11 (PARP11) acts as an essential regulator of TI-Tregs regulatory and protumorigenic activities. Expression of PARP11 correlated with TI-Treg infiltration and poor responses to immune checkpoint blockade (ICB) in human cancer patients. PARP11 was induced in the TI-Treg cells by tumor-derived factors including adenosine and prostaglandin E2. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivated TI-Treg cells and reinvigorated anti-tumor immune responses. Accordingly, ITK7 decelerated tumor growth and significantly increased the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of CAR T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

2023-12-07 | GSE249299 | GEO

Eum2

Project description:The low immunogenicity of many cancer cells and the immunosuppression by various cancers and anti-cancer therapies have been an obstacle in the development of efficacious immunotherapies. Our goal was to test if TLR agonists and anti-cancer chemotherapeutic agents synergize in rendering tumor cells more immunogenic.

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Project description:Prognosis of metastatic BRAF V600E mutant colorectal cancer (CRC) is poor, and the prognostic implications of immune contextures in the tumor microenvironment (TME) for CRC remain elusive. Complement activation in the TME was significantly associated with poor OS and was correlated with TAM M2 in patients with de novo metastatic BRAF V600E mutant CRC.

2022-11-08 | GSE211576 | GEO

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2023-05-01 | E-MTAB-10467 | biostudies-arrayexpress

Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function [DNA-edit]

Project description:Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. Additionally, ADA-OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA-OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. We then show ADA-OE improves tumor infiltration and clearance by α-HER2 CD4 and CD8 CAR-T with an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.

2023-05-18 | GSE225185 | GEO

Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function [RNA-seq]

2023-05-18 | GSE225184 | GEO

TIGIT Blockade Exerts Synergistic Effects on Microwave Ablation against Cancer

Project description:Combination immunotherapy based on immune checkpoint inhibitors (ICIs) has shown great success in the treatment of many types of cancers and has become the mainstream in the comprehensive treatment of cancers. Ablation in combination with immunotherapy has achieved tremendous efficacy in some preclinical and clinical studies. To date, our team proved that ablation in combination with ICIs was a promising antitumor therapeutic strategy for the liver metastasis of colorectal cancer (CRC). Moreover, we found that the expression of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) expression was up-regulated after microwave ablation (MWA), indicating that TIGIT was involved in immunosuppression, and the combination of MWA and TIGIT blockade represented a potential clinical treatment strategy. In this study, we analyzed the single-cell RNA sequencing (scRNA-seq) data from the MWA and MWA plus anti-TIGIT groups. We found that TIGIT blockade in combination with MWA significantly promoted the expansion and functions of CD8+ TILs and reshaped myeloid cells in the tumor microenvironment (TME). In conclusion, TIGIT blockade in combination with MWA was a novel treatment strategy for the liver metastasis of CRC, and this combination therapy could reprogram the TME toward an antitumor environment.

2022-03-30 | GSE194209 | GEO

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