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Published on: September 7, 2013
The skin microbiota drives cutaneous immune checkpoint inhibitor toxicity in genetically susceptible mice
Vanessa Salazar1, Scott T Espenschied2, Anthony P Fernandez3
1Department of Inflammation and Immunity, Cleveland Clinic Research, Cleveland, OH, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Abstract:
Immune checkpoint inhibitors (ICIs) show increasing promise for cancer therapy. However, patients can experience adverse events, particularly those with pre-existing autoimmune disease. We determined that the microbiome can drive ICI-induced systemic toxicity in a mouse model of autoimmune susceptibility. Specifically, ICI treatment of specific pathogen-free (SPF) Act1-/- mice, which develop spontaneous autoimmunity due to a deficiency in an immune adaptor, resulted in systemic adverse events that were ameliorated by topical antibiotics. Moreover, germ-free (GF) Act1-/- mice failed to develop ICI toxicity. Transfer of gut or skin microbiota from SPF Act1-/- mice to GF Act1-/- mice showed that only the skin microbiota rendered exGF mice sensitive to ICI toxicity. Notably, therapeutic application of topical antibiotics decoupled ICI-induced toxicity from anti-tumor efficacy in SPF Act1-/- mice. This model provides a paradigm for future translational studies in cancer patients to mitigate adverse effects of ICIs and maximize their efficacy by targeting skin microbes.
Insights
The skin microbiome drives immune checkpoint inhibitor toxicity in autoimmune-prone mice. Topical antibiotics reduced side effects without compromising anti-tumor effects, offering a new therapeutic strategy.
Area of Science:
- Immunology
- Microbiome Research
- Cancer Therapy
Background:
- Immune checkpoint inhibitors (ICIs) are promising cancer therapies.
- Patients with autoimmune diseases may experience adverse events during ICI treatment.
Purpose of the Study:
- To investigate the role of the microbiome in ICI-induced systemic toxicity.
- To explore strategies for mitigating ICI-related adverse events.
Main Methods:
- Utilized a mouse model (Act1-/-) with autoimmune susceptibility.
- Compared ICI toxicity in specific pathogen-free (SPF) versus germ-free (GF) mice.
- Investigated the impact of gut and skin microbiota transfer.
- Assessed the effect of topical antibiotics on ICI toxicity and anti-tumor efficacy.
Main Results:
- SPF Act1-/- mice treated with ICIs developed systemic adverse events.
- ICI toxicity was absent in GF Act1-/- mice.
- Transfer of skin microbiota, but not gut microbiota, from SPF to GF mice induced ICI sensitivity.
- Topical antibiotics ameliorated ICI-induced toxicity without affecting anti-tumor efficacy.
Conclusions:
- The skin microbiome plays a critical role in mediating ICI-induced systemic toxicity.
- Targeting skin microbes with topical antibiotics may mitigate adverse events and enhance ICI therapy efficacy.
- This study provides a translational model for managing ICI side effects in cancer patients.
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