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Effect of ECP on intestinal immune cells in immune checkpoint inhibitor-induced colitis - batch2 [scRNA-Seq]

ABSTRACT: Immune Checkpoint Inhibitors (ICI) have proven to be beneficial against tumors by boosting anti-tumor immunity, however these therapies can induce severe inflammatory side effects in all tissues, named immune-related adverse events (irAE). The colon is affected most commonly. These cause termination of treatment. Until today, patients with irAEs received systemic immunosuppressive therapies. We have found ECP as a novel therapy, which causes immunomodulation in the inflamed tissue without systemic immunosuppression. To understand which immune cells are affected by ECP in the inflamed intestinal tract, mice were treated with DSS and anti-PD1 to induce colitis, comparable to patients suffering from ICI-induced irAEs. ECP showed beneficial effects in patients. Mice were transplanted with ECP-treated cells as treatment and scSeq was performed with Colon infiltrating CD45 positive cells. Naive mice, mice receiving DSS and isotype control and mice receiving DSS in combination with anti-PD1 and untreated splenocytes, served as control.

ORGANISM(S): Mus musculus

PROVIDER: GSE256286 | GEO | 2024/11/27

REPOSITORIES: GEO

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Project description:Immunotherapies, including immune checkpoint inhibitors (ICI), have revolutionized the treatment of many cancers, producing significant improvements in survival in patients with many different cancers. However, the intended anti-tumor effects also result in a unique form of autoimmunity, known as immune-related adverse events (irAEs), which have emerged as a limiting factor for many immunotherapies. Cutaneous irAEs (cirAEs), the most frequently occurring ICI–related toxicities, have been associated with improved efficacy and survival but, in their severe forms, require systemic steroids and have in cases led to premature ICI discontinuation and fatality. There is a need for both robust biomarkers and adequate models that effectively predict which patients who develop irAEs may have improved outcomes. Using a microfluidic droplet technology that generates "mini" patient-derived organoids called MicroOrganoSpheres (MOSTM), we successfully generated skin MOS from skin biopsy samples in both healthy skin and tumor-involved skin that sustain the original patient skin immune microenvironment over three weeks. Using this model, we assessed skin cell toxicity and cytokine release in response to ICI and targeted therapies. Clinical responses were largely consistent with the skin and tumor MOS assay readouts, indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Matched pairs of patient melanoma and skin MOS showed good concordance with patient outcome indicating that MOS recapitulates the potential association between skin irAEs and efficacy. Enrichment of genes associated with atopic dermatitis, vitiligo, and psoriatic dermatitis were observed in MOS generated from skin of an ICI-sensitive patient compared to the MOS generated from skin of an ICI-resistant patient. These results indicated that the skin MOS platform can potentially predict the dermatological toxicity of ICI. As the MOS assay can be completed within 12 days after biopsy acquisition, this novel technology may enable personalized medicine approaches by prediction of cirAEs and efficacy for individual patients.

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Effect of ECP on intestinal immune cells in immune checkpoint inhibitor-induced colitis - batch2 [scRNA-Seq]

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