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Checkpoint blockade-induced dermatitis and colitis are dominated by tissue resident memory T cells and Th1/Tc1 cytokines

ABSTRACT: Immune checkpoint blockade (ICB) is therapeutically successful in multiple cancer types. However, immune-related adverse events (irAE) frequently occur and can sometimes be life-threatening. It is critical to understand the immunologic mechanisms of irAEs with the goal of finding novel treatment targets. Therefore, we studied tissues from irAE dermatitis cases using multiparameter immunofluorescence (IF), spatial transcriptomics, and RNA in situ hybridization. Skin psoriasis cases were studied as a comparison, as a known Th17-driven disease, and colitis was investigated as a comparison. IF analysis revealed that CD4+ and CD8+ tissue resident memory T (TRM) cells were preferentially expanded in the inflamed portion of skin in cutaneous irAEs compared to healthy skin controls. Spatial transcriptomics allowed focusing attention on areas containing TRM cells to discern their functional phenotype, and revealed expression of Th1-associated genes in irAE, compared to Th17-asociated genes in psoriasis. Expression of a range of inhibitory checkpoint molecules was observed, including PD-1, CTLA-4, LAG-3, and TIGIT. RNA in situ hybridization (RISH) technology combined with IF confirmed expression of IFN-γ, CXCL9, CXCL10, and TNF-α in additional irAE dermatitis cases and allowed us to identify production of IFN-γ within TRM cells specifically. The Th1-skewed phenotype was confirmed in irAE colitis cases compared to healthy colon.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210037 | GEO | 2022/08/08

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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Checkpoint blockade-induced dermatitis and colitis are dominated by tissue resident memory T cells and Th1/Tc1 cytokines

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