HNRNPA2B1 enhances immune evasion in colorectal cancer
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ABSTRACT:
PROVIDER: PRJNA1200040 | ENA |
REPOSITORIES: ENA
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Project description:Immune checkpoint blockade has shown remarkable efficacy in a subset of colorectal cancers (CRCs) with high microsatellite instability (MSI-H), yet the majority of CRCs remain unresponsive, in part due to poor tumor–immune cell crosstalk. Here we identify HNRNPA2B1, an RNA-binding protein prominently upregulated in CRC, as a key modulator of the tumor immune microenvironment. Despite being central within a dysregulated network of RNA-binding proteins, HNRNPA2B1 exhibits minimal cytotoxicity to normal cells. Using mouse models and single-cell RNA-sequencing, we reveal that HNRNPA2B1 depletion enhances Cxcl9/Cxcl10–Cxcr3 signaling, elevates CD8^+ T-cell infiltration and activation, and improves antigen presentation via MHC class I.
2025-09-09 | GSE284681 | GEO
Project description:ID3 Enhances PD-L1 Expression by Restructuring MYC and Promotes Colorectal Cancer Immune Evasion [ChIP-seq]
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Project description:ID3 Enhances PD-L1 Expression by Restructuring MYC and Promotes Colorectal Cancer Immune Evasion [RNA-seq]
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Project description:Microsatellite stable (MSS) colorectal cancer (CRC) is often characterized as a "cold" tumor, exhibiting minimal responsiveness to monotherapy with PD-1 antibodies. The underlying mechanisms of this intrinsic unresponsiveness to immunotherapy have been elusive. Here, we report that cathepsin D (CTSD) is highly expressed in MSS CRC, significantly contributing to its resistance to immunotherapy. Specifically, CTSD facilitates immune evasion by shielding cancer cells from cytotoxic T-cell-mediated killing. Mechanistically, as a protease, CTSD interacts with the α2 domain of the major histocompatibility complex class I (MHC-I) molecule via its catalytic domain's light chain, promoting the degradation of MHC-I through lysosomal pathways and disrupting the recycling of MHC-I to the cell surface. Notably, deletion or pharmacological inhibition of CTSD with pepstatin A prevents this immune evasion and enhances the efficacy of anti-PD-1 antibodies. Collectively, these findings highlight the role of CTSD in immune evasion and provide a compelling rationale for the development of a novel combination therapy involving CTSD inhibition and anti-PD-1 immunotherapy in CRC.
2025-10-18 | GSE306871 | GEO
Project description:The inhibitor of DNA-binding protein ID3 is a vital component of immune cells and has been associated with the progression of colorectal cancer (CRC). Despite its significance, its specific role in the immune evasion strategies utilized by CRC remains unclear. RNA-seq analysis revealed that ID3 is associated with the PD-L1 immune checkpoint. We further demonstrated that ID3 modulates PD-L1 expression, suppresses the infiltration and activation of CD8+ T cells, and facilitates the immune escape of CRC cells. Additionally, we found that the knockdown of ID3 significantly enhanced the effectiveness of PD-L1 antibody treatment in combating CRC, reduced the upregulation of PD-L1 induced by the antibody, and altered the immune microenvironment within CRC. Mechanistically, our biological and structural analyses demonstrated that ID3 reconstructed the four-dimensional structure of MYC, thereby enhancing its binding affinity to the PD-L1 promoter and augmenting PD-L1 transcriptional activity. By integrating analysis of ChIP-seq, RNA-seq, and ImmPort gene sets, we found that ID3's DNA-assisted binding function was widespread and could either enhance or suppress gene transcription, not only affecting tumor immune escape through immune checkpoints, but also regulating various cytokines and immune cells involved in tumor immunity. In conclusion, our study uncovered a new mechanism by which ID3 promotes immune evasion in CRC and targeting ID3 may improve the efficacy of anti-PD-1/PD-L1 immunotherapy.
2024-09-30 | GSE275454 | GEO
Project description:The inhibitor of DNA-binding protein ID3 is a vital component of immune cells and has been associated with the progression of colorectal cancer (CRC). Despite its significance, its specific role in the immune evasion strategies utilized by CRC remains unclear. RNA-seq analysis revealed that ID3 is associated with the PD-L1 immune checkpoint. We further demonstrated that ID3 modulates PD-L1 expression, suppresses the infiltration and activation of CD8+ T cells, and facilitates the immune escape of CRC cells. Additionally, we found that the knockdown of ID3 significantly enhanced the effectiveness of PD-L1 antibody treatment in combating CRC, reduced the upregulation of PD-L1 induced by the antibody, and altered the immune microenvironment within CRC. Mechanistically, our biological and structural analyses demonstrated that ID3 reconstructed the four-dimensional structure of MYC, thereby enhancing its binding affinity to the PD-L1 promoter and augmenting PD-L1 transcriptional activity. By integrating analysis of ChIP-seq, RNA-seq, and ImmPort gene sets, we found that ID3's DNA-assisted binding function was widespread and could either enhance or suppress gene transcription, not only affecting tumor immune escape through immune checkpoints, but also regulating various cytokines and immune cells involved in tumor immunity. In conclusion, our study uncovered a new mechanism by which ID3 promotes immune evasion in CRC and targeting ID3 may improve the efficacy of anti-PD-1/PD-L1 immunotherapy.
2024-09-30 | GSE275455 | GEO
Project description:SOX17 initiates an immune evasion program in early colorectal cancers.
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Project description:Our previous study showed the immunosuppressive ability of colorectal cancer cell-intrinsic ATP6V0A1. This project aimed to understand the mechanism of ATP6V0A1 regulating immune evasion in colorectal cancer (CRC). For this purpose, we used MS analysis to detect the changes in the protein expression profile induced by Atp6v0a1 knockdown in MC38 cells.
2024-06-11 | PXD044010 |
Project description:To identify HNRNPA2B1 binding sites on endogenous nuclear RNAs, we performed HITS-CLIP for endogenous HNRNPA2B1 and RNA-seq to analyze the nuclear RNA under either METTL3 or HNRNPA2B1 depletion. Wild type MDA-MB-231 cells were subjected to the HITS-CLIP procedure on immunoprecipitated HNRNPA2B1 associated RNA obtained from the nuclear fraction (Licatalosi D, et al. 2008, Nature 456:464-U22). For RNA-seq, nuclear RNA was extracted from MDA-MB-231 or Hela cells knocked down for METTL3 or HNRNPA2B1.
2015-06-20 | E-GEOD-70061 | biostudies-arrayexpress
Project description:SOX17 initiates an immune evasion program in early colorectal cancers [RNAseq_200615Yil]
| PRJNA923247 | ENA