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Inflammatory epiCaspase-1 dampens immunogenic cell death by remotely skewing bone marrow hematopoiesis to drive systemic neutrophil-dominant inflammation [T24 RNAseq]

ABSTRACT: While local immunological effects of chemotherapy-induced tumor cell death are well studied, its systemic impact on distant bone marrow—a site essential for immune cell maturation—remains underexplored. Here, we show that gemcitabine chemotherapy induces inflammatory caspase-1 activation in epithelial cancer cells (epiCaspase-1), triggering pyroptotic cell death. Despite its inflammatory nature, epiCaspase-1 mediated cell death is non-immunogenic. Clinically, cancer patients with high expression of a newly derived epiCaspase-1 gene signature show poorer outcomes. Mechanistically, epiCaspase-1 induces noncanonical release of IL-1α through NINJ1 lytic pores, which remotely skews bone marrow hematopoiesis towards granulocyte-monocyte progenitors and mature neutrophil output. This systemic alteration leads to a heightened neutrophil-to-lymphocyte ratio (NLR) in both peripheral blood and the tumor microenvironment. Notably, pharmaceutic inhibition of caspase-1 blocks this cascade, normalizes hematopoiesis, and recalibrates NLR to favor intratumoral CD8+ T cell infiltration and activation—ultimately improving chemotherapeutic efficacy. These findings underscore that inflammatory pyroptosis is not inherently immunogenic, instead, it reshapes systemic immune landscape towards neutrophil-dominant inflammation in the chemotherapy context.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299107 | GEO | 2026/02/06

REPOSITORIES: GEO

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Inflammatory epiCaspase-1 dampens immunogenic cell death by remotely skewing bone marrow hematopoiesis to drive systemic neutrophil-dominant inflammation

Project description:While local immunological effects of chemotherapy-induced tumor cell death are well studied, its systemic impact on distant bone marrow—a site essential for immune cell maturation—remains underexplored. Here, we show that gemcitabine chemotherapy induces inflammatory caspase-1 activation in epithelial cancer cells (epiCaspase-1), triggering pyroptotic cell death. Despite its inflammatory nature, epiCaspase-1 mediated cell death is non-immunogenic. Clinically, cancer patients with high expression of a newly derived epiCaspase-1 gene signature show poorer outcomes. Mechanistically, epiCaspase-1 induces noncanonical release of IL-1α through NINJ1 lytic pores, which remotely skews bone marrow hematopoiesis towards granulocyte-monocyte progenitors and mature neutrophil output. This systemic alteration leads to a heightened neutrophil-to-lymphocyte ratio (NLR) in both peripheral blood and the tumor microenvironment. Notably, pharmaceutic inhibition of caspase-1 blocks this cascade, normalizes hematopoiesis, and recalibrates NLR to favor intratumoral CD8+ T cell infiltration and activation—ultimately improving chemotherapeutic efficacy. These findings underscore that inflammatory pyroptosis is not inherently immunogenic, instead, it reshapes systemic immune landscape towards neutrophil-dominant inflammation in the chemotherapy context.

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Inflammatory epiCaspase-1 dampens immunogenic cell death by remotely skewing bone marrow hematopoiesis to drive systemic neutrophil-dominant inflammation

Project description:Inflammatory epiCaspase-1 dampens immunogenic cell death by remotely skewing bone marrow hematopoiesis to drive systemic neutrophil-dominant inflammation

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Inflammatory epiCaspase-1 dampens immunogenic cell death by remotely skewing bone marrow hematopoiesis to drive systemic neutrophil-dominant inflammation [T24 RNAseq]

Project description:Inflammatory epiCaspase-1 dampens immunogenic cell death by remotely skewing bone marrow hematopoiesis to drive systemic neutrophil-dominant inflammation [T24 RNAseq]

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