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Reply to ‘Personalized treatment of immune-related adverse events — balance is required’

Nature Reviews Clinical Oncology volume 17, page 518 (2020)Cite this article

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We wish to respond to the letter on our Review (Moving towards personalized treatments of immune-related adverse events. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/s41571-020-0352-8 (2020))1 from Martins and Obeid (Personalized treatment of immune-related adverse events — balance is required. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/s41571-020-0400-4 (2020))2. The study of immune-related adverse events (irAEs) in patients receiving immune-checkpoint inhibitors (ICIs) is incredibly complex and fast moving. While we acknowledge the contribution of Martins et al.3 in this field, many groups (including ours) have collaboratively worked and reported on fine-tuning the personalized treatments of irAEs by dissecting the drivers of toxicities4,5,6. In their Review and letter, the proposed algorithm is reliant on findings of light microscopy from affected organs, which is both practical and easily feasible. However, we posit that irAEs provide us with a unique window of opportunity for studying autoimmunity, and advanced immunophenotyping techniques (including flow cytometry, multiplex cytokine analysis or advanced immunohistochemistry, among others) should be leveraged to better understand the drivers of toxicities, especially in immunosuppression-refractory cases or those involving critical organs such as in the cases we cite above4,5,6. With this motivation in mind, we have provided a much-needed update to this field by critically appraising the complex immunohistopathological mechanisms by which irAEs are induced in patients receiving ICIs, as well as covering emerging fields such as those of innate immunity and the microbiome1.

The assertion of Martins and Obeid2 regarding the dangers of antagonizing cytokines associated with innate immunity (such as IL-5), which might not effectively suppress T cell function, seems to be based on the assumption that all irAEs are T cell mediated and are the result of a breach of self-tolerance. The current evidence points towards an important role of innate immune cells in potentially driving both antitumour responses and irAEs in patients receiving ICIs, as highlighted in our Review1. As such, some irAEs are possibly the result of activation of innate immune responses, leading to an autoinflammatory phenotype, with limited or no contribution of self-directed T cell processes. In these situations, we consider that not exposing patients to the deleterious adverse effects of additional immunosuppression might be an important future approach, where “balance is required”2. Discriminating between potential causes for irAEs requires leveraging advanced immunophenotyping techniques beyond light microscopy, which is the approach we encourage.

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References

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Authors and Affiliations

  1. Department of Medicine, Division of Oncology, Jewish General Hospital and Rossy Cancer Network, Montreal, Quebec, Canada

    Kashayar Esfahani

  2. Department of Immunology and Rheumatology, Cleveland Clinic, Cleveland, OH, USA

    Leonard Calabrese

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  1. Kashayar Esfahani
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  2. Leonard Calabrese
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Correspondence to Kashayar Esfahani.

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Esfahani, K., Calabrese, L. Reply to ‘Personalized treatment of immune-related adverse events — balance is required’. Nat Rev Clin Oncol 17, 518 (2020). https://doi.org/10.1038/s41571-020-0401-3

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