The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis.
Aged
Bronchoalveolar Lavage
CD4-Positive T-Lymphocytes
/ immunology
Cytokines
/ immunology
Female
Humans
Immunotherapy
/ adverse effects
Male
Middle Aged
Neoplasms
/ immunology
Pneumonia
/ chemically induced
Programmed Cell Death 1 Receptor
/ immunology
Prospective Studies
Pulmonary Alveoli
/ immunology
Cancer immunotherapy
Immunology
Lung cancer
Pulmonology
Th1 response
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
16 07 2019
16 07 2019
Historique:
entrez:
17
7
2019
pubmed:
17
7
2019
medline:
17
6
2020
Statut:
epublish
Résumé
Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown. To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n=12) and without CIP (n=6), prior to initiation of first-line therapy for CIP (high dose corticosteroids. We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis and BAL supernatant cytokine measurements. We found increased BAL lymphocytosis, predominantly CD4+ T cells, in CIP. Specifically, we observed increased numbers of BAL central memory T-cells (Tcm), evidence of Type I polarization, and decreased expression of CTLA-4 and PD-1 in BAL Tregs, suggesting both activation of pro-inflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counter-regulatory IL-1RA. We observed increased levels of T cell chemoattractants in the BAL supernatant, consistent with our pro-inflammatory, lymphocytic cellular landscape. We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune related adverse event.
Sections du résumé
BACKGROUND
Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown.
METHODS
To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n=12) and without CIP (n=6), prior to initiation of first-line therapy for CIP (high dose corticosteroids. We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis and BAL supernatant cytokine measurements.
RESULTS
We found increased BAL lymphocytosis, predominantly CD4+ T cells, in CIP. Specifically, we observed increased numbers of BAL central memory T-cells (Tcm), evidence of Type I polarization, and decreased expression of CTLA-4 and PD-1 in BAL Tregs, suggesting both activation of pro-inflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counter-regulatory IL-1RA. We observed increased levels of T cell chemoattractants in the BAL supernatant, consistent with our pro-inflammatory, lymphocytic cellular landscape.
CONCLUSION
We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune related adverse event.
Identifiants
pubmed: 31310589
pii: 128654
doi: 10.1172/JCI128654
pmc: PMC6763233
doi:
pii:
Substances chimiques
Cytokines
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Types de publication
Clinical Trial
Journal Article
Multicenter Study
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4305-4315Subventions
Organisme : NIAMS NIH HHS
ID : P30 AR070254
Pays : United States
Commentaires et corrections
Type : CommentIn
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