The paradox of immune checkpoint inhibition reactivating tuberculosis

Abstract

By attenuating T cell activation, immune checkpoints (ICs) limit optimal anti-tumor responses, and immune checkpoint inhibition (ICI), has emerged as a highly effective new therapy for a broad range of cancers. However, boosting T cell immunity in cancer patients by blocking the PD-1/PDL-1 axis can trigger reactivation of latent tuberculosis (TB). This phenomenon appears to contradict the prevailing thought that enhancing T cell immunity to Mycobacterium tuberculosis (Mtb) will improve immune control of this pathogen. In support of this anecdotal human data, several murine studies have shown that PD-1 deficiency leads to severe TB disease and rapid death. These observations warrant a serious reconsideration of what constitutes effective TB immunity and how ICs contribute. Through restraining T cell responses, ICs are critical to preventing excessive tissue damage and maintaining a range of effector functions. Supporting this notion, inhibitory receptors limit pathology in respiratory infections such as influenza, where loss of negative immune regulation resulted in progressive immunopathology. In this review, we analyze the mechanisms of ICs in general and their role in TB in particular. We conclude with a reflection on the emerging paradigm and avenues for future research.

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ORCID for Paul Elkington: orcid.org/0000-0003-0390-0613

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