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Cancer Immunology Research
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Cancer Immunology at the Crossroads

Understanding and Overcoming the Inflammatory Toxicities of Immunotherapy

Michael Dougan
Michael Dougan
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: mldougan@partners.org
DOI: 10.1158/2326-6066.CIR-20-0372 Published October 2020
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Abstract

Checkpoint blockade immunotherapy has led to impressive therapeutic responses in a wide variety of tumors, but also leads to a spectrum of inflammatory toxicities that can involve any organ system in the body. Although most inflammatory toxicities resolve with systemic immune suppression, fatal toxicities can occur, and interruption and discontinuation of immunotherapy because of toxicity are common. In addition to their clinical impact, these inflammatory toxicities also provide a window into immune regulation in humans. By studying the cellular and molecular mechanisms that drive this inflammation, we have an opportunity to learn how the immune checkpoints, cytotoxic T lymphocyte antigen-4 and programmed death-1 and its ligand, maintain immune homeostasis throughout the body. Although we have an increasingly detailed understanding of the mechanisms that drive effective antitumor immunity, we have a rudimentary picture of the mechanisms of toxicity. Most toxicities involve barrier organs, suggesting an important role for interactions with the environment, including the microbiome. Early analyses have implicated cytotoxic T cells, although the antigens recognized by these cells, and the pathways activated by and around them are still unknown. By gaining a detailed understanding of the immune mechanisms of toxicity, we have the potential to develop novel interventions for them. These treatments should take advantage of differences between effective antitumor immunity and the principal drivers of organ inflammation. By targeting these mechanistic differences, we can develop therapies that can be used alongside immunotherapy, blocking inflammatory toxicity while preserving or even enhancing the response to cancer.

Footnotes

  • Cancer Immunol Res 2020;8:1230–5

  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (10)
October 2020
Volume 8, Issue 10
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Understanding and Overcoming the Inflammatory Toxicities of Immunotherapy
Michael Dougan
Cancer Immunol Res October 1 2020 (8) (10) 1230-1235; DOI: 10.1158/2326-6066.CIR-20-0372

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Understanding and Overcoming the Inflammatory Toxicities of Immunotherapy
Michael Dougan
Cancer Immunol Res October 1 2020 (8) (10) 1230-1235; DOI: 10.1158/2326-6066.CIR-20-0372
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    • Abstract
    • Introduction
    • Mechanism of Organ Injury From Checkpoint Blockade
    • Managing Toxicities to Improve Antitumor Immunity
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Cancer Immunology Research
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