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Inflammatory cytokines induce novel cancer dependencies

ABSTRACT: Tumor cells respond and adapt to environmental stresses, including cytokine-mediated inflammation, to facilitate growth in hostile environments. However, cytokine responses also induce transcriptional and cell state changes that may predispose tumor cells to new vulnerabilities, which remain largely unexplored. Here, we performed in vitro genome-scale CRISPR loss-of-function screens in eight cancer models exposed to IFNγ, IFNβ, or TNFα to map context-specific genetic vulnerabilities. We identified members of the GPI transamidase complex and the lipid phosphatase FITM2 as interferon-specific cancer dependencies. Tumor-specific deletion of GPI transamidase subunits or FITM2 dramatically enhanced response to immune checkpoint blockade in vivo. By integrating functional genomics, metabolomics and pharmacological blockade, we determined that loss of FITM2 predisposed cancer cells to IFNγ-driven endoplasmic reticulum and oxidative stress, culminating in a paraptosis-like cell death. Our study provides a comprehensive profiling of tumor-intrinsic dependencies governing responses to inflammatory cytokines, thereby presenting promising avenues for therapeutic intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE269110 | GEO | 2025/09/04

REPOSITORIES: GEO

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Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.

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Inflammatory cytokines induce novel cancer dependencies

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