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Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

ABSTRACT: Immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 are essential components of the cancer therapeutic armamentarium. The remarkable responses seen with ICIs however, are also accompanied by immune-related adverse events (irAEs). These inflammatory side-effects impact virtually all organ systems, with the most common being the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint blockade aberrantly unleashes commensal-specific T cell responses. Such responses caused widespread immune cell infiltration and inflammation throughout the skin, recapitulating the skin irAEs seen in patients treated with ICIs. This skin inflammation was dependent on production of the cytokine IL-17 by commensal-specific T cells, which in turn induced hyperactive responses from macrophages and myeloid cells. Importantly, these responses had long-term consequences, with commensal-specific T cells elicited in the context of ICIs being highly sensitive to re-activation by commensals months later. Together, our results establish a mouse model of skin irAEs and show that immune checkpoint blockade can potentiate aberrant immunity to skin commensals with long-lasting consequences.

ORGANISM(S): Mus musculus

PROVIDER: GSE176030 | GEO | 2022/06/20

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.

Project description:All healthy individuals have autoreactive T cells in their peripheral T cell pool, but peripheral tolerance mechanisms prevent these T cells from causing autoimmunity. Two primary mechanisms of peripheral tolerance are T cell anergy and clonal deletion, which occur after tolerogenic priming of T cells by dendritic cells (DCs). Induction of anergy and deletion are impaired in the absence of checkpoint receptors (like PD-1), but, once established, they are not reversed by blockade of checkpoint receptors. Thus, the occurrence of immune-related Adverse Events (irAEs) in up to 70% of patients treated with checkpoint inhibitor (CPI) immunotherapy has raised questions about how checkpoint receptors are functioning to maintain peripheral tolerance of autoreactive T cells under homeostatic conditions. To address this, we developed a novel mouse model for studying peripheral T cell tolerance in the skin in which the development of localized autoimmune-like pathology was dependent on skin-infiltrating CD8 T cells following skin-specific expression of T cell antigens (Ags) and administration of PD-1 blocking antibodies. Interestingly, Ag-specific CD8 T cells were found to infiltrate Ag-expressing skin even in the absence of PD-1 blockade, however they did not cause disease and in fact co-existed with the skin cells expressing their cognate Ag. At the protein level, non-pathogenic skin-infiltrating CD8 T cells produced lower amounts of many T cell effector proteins compared to their pathogenic counterparts, explaining the lack of cutaneous pathology, but non-pathogenic T cells were functional because they remodeled the local myeloid cell compartment. Moreover, and unlike in other models of tolerance, non-pathogenic and pathogenic skin-infiltrating CD8 T cells were nearly identical at the transcriptional level, indicating that both T cell populations were differentiating towards the same effector state. In this context, checkpoint receptors prevented the majority of the non-pathogenic CD8 T cells from reaching their terminal, fully effector and pathogenic state, thus maintaining tolerance in the skin. Finally, analysis of skin biopsies from two patients with cutaneous lichenoid irAEs showed presence of clonally expanded effector CD8 T cells with comparable transcriptional profiles in both lesional and non-lesional skin. Thus, our data are in line with a model of peripheral T cell tolerance where PD-1 allows peripheral Ag-specific effector CD8 T cells to co-exist in a tissue where their cognate Ag is expressed without causing pathology and provide a mechanism for the development of cutaneous lichenoid irAEs upon administration of CPI immunotherapy.

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Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

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