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Pathologically Activated Neutrophils Induce Contact-Dependent Suppression of Cytotoxic T Cells

ABSTRACT: The immunosuppressive tumor microenvironment remains a major obstacle to successful immunotherapy. Pathologically activated neutrophils, alternatively termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), drive tumor immune evasion principally through induction of CD8+ T cell tolerance. While direct intercellular contact between neutrophils and CD8+ T cells is essential for immunosuppressive activity, the mechanisms mediating this interaction need for deeper understanding. Here, we identify CD300ld, an immune inhibitory receptor on neutrophils, mediates neutrophil-driven contact-dependent suppression of cytotoxic CD8+ T cells via binding to phosphatidylserine (PS). Mice with mutant CD300ld, which lack PS-binding capacity, exhibit reduced immunosuppressive activity, phenocopying CD300ld knockout mice in multiple tumor models. Blockade of the PS-CD300ld interaction by neutralizing antibodies demonstrate therapeutic efficacy against established tumors and synergize with anti-PD-1 therapy. Clinical analyses reveal elevated CD300LD expression inversely associates with intertumoral PShigh CD8+ T cell infiltration and predicts poor responses to checkpoint blockade therapy. Our findings establish CD300ld-PS mediated T cell contact as a critical mechanism of neutrophil-driven immune evasion, revealing a targetable checkpoint pathway to overcome tumor immune resistance and improve immunotherapy outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE295996 | GEO | 2026/03/26

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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Pathologically Activated Neutrophils Induce Contact-Dependent Suppression of Cytotoxic T Cells

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