The paradox of immune checkpoint inhibition reactivating tuberculosis
The paradox of immune checkpoint inhibition reactivating tuberculosis
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.
Humans, Mice, Animals, Programmed Cell Death 1 Receptor/metabolism, Immune Checkpoint Inhibitors, Tuberculosis/drug therapy, Mycobacterium tuberculosis, Lymphocyte Activation
Ahmed, Mohamed
32ed6621-7378-450f-8b0e-f6fec6e271de
Tezera, Liku B
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Elkington, Paul T
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Leslie, Alasdair J
00f79867-4024-4596-80b6-bc279515da01
10 November 2022
Ahmed, Mohamed
32ed6621-7378-450f-8b0e-f6fec6e271de
Tezera, Liku B
c5598dbf-23a8-4934-96a4-7c783bf9e776
Elkington, Paul T
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Leslie, Alasdair J
00f79867-4024-4596-80b6-bc279515da01
Ahmed, Mohamed, Tezera, Liku B, Elkington, Paul T and Leslie, Alasdair J
(2022)
The paradox of immune checkpoint inhibition reactivating tuberculosis.
European Respiratory Journal, 60 (5).
(doi:10.1183/13993003.02512-2021).
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.
Text
ERJ-02512-2021_Author_accepted
- Accepted Manuscript
More information
Accepted/In Press date: 6 April 2022
e-pub ahead of print date: 18 April 2022
Published date: 10 November 2022
Additional Information:
Funding for this research was provided by: Sub-Saharan African Network for TB/HIV Research Excellence
Wellcome Trust (210662/Z/18/Z)
Keywords:
Humans, Mice, Animals, Programmed Cell Death 1 Receptor/metabolism, Immune Checkpoint Inhibitors, Tuberculosis/drug therapy, Mycobacterium tuberculosis, Lymphocyte Activation
Identifiers
Local EPrints ID: 456896
URI: http://eprints.soton.ac.uk/id/eprint/456896
ISSN: 0903-1936
PURE UUID: 613c8121-ab95-4107-b58f-856706f7b931
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Date deposited: 16 May 2022 16:39
Last modified: 28 Feb 2025 05:05
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Contributors
Author:
Mohamed Ahmed
Author:
Alasdair J Leslie
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