Myeloid-Dependent Immunosuppressive Features Drive and Predict IPF Progression
American Journal of Respiratory and Critical Care Medicine
; 205(1), 2022.
Article
in English
| EMBASE | ID: covidwho-1927859
ABSTRACT
Rationale Despite the availability of pharmacologic therapies, idiopathic pulmonary fibrosis (IPF) is still a clinical challenge with several unmet needs. Robust evidence supports monocytes as cellular biomarkers of progression in IPF. Yet, their precise role and whether specific subtypes might predict progression and drive disease is unknown. We reported, for the first time, that myeloidderived suppressor cells (MDSC), immature precursors of monocytes, are increased in numbers, functionally active in IPF. Monocytic MDSC is the predominant subtype in IPF, and yet, functional characterization and immune modulation properties have not been explored. Methods and Results:
characterization of circulating myeloid populations in IPF by multicolor FACS confirmed the abundance of MDSC (Lin-, HLA-DRlo, CD33+, CD14+, S100A+, CD28L1+ and ICOSL+) in IPF (n=78) and fILD (n=83), also abundant in whole blood scRNA seq of severe Covid-19 patients that progressed into fibrosis, and not in mild Covid-19. Then, we prospectively followed 83 fILD patients (45% IPF, 55% non-IPF -EAA, CTD-ILD, NSIP-) over 1 year and immunophenotyped them every 3 months. Cross-sectional analysis showed that patients with a higher number circulating MDSC, had a higher GAP index (7-8) (p<0,001). Longitudinal follow-up showed that patients with constant higher circulating MDSC had lower transplant-free survival (p=0.0058). Primary isolated MDSC when co-cultured with autologous T cells induced CD8+ T cell exhaustion (PD1hi, Lag3hi, Tim3hi, TNFalpha lo, INFglo), and downregulation of co-stimulatory T cell signaling (CD28, ICOS, ITK, and LCK), preliminary data support the induction of de-novo FoxP3 Treg formation, creating a suppressive and immunosenescent microenvironment in IPF. FACS analysis of explanted lungs demonstrated the increase of tissue-resident MDSC in fibrosis (HP, NSIP, IPF) compared with donor lungs, as well as in bleomycin-induced fibrosis compared to PBS.Conclusion:
Taking together, a high number of circulating MDSC reflects worse lung function and higher GAP index in cross-sectional analysis, and associates with lower transplant-free survival longitudinally. The role that immature and mature monocytes play during promotion of a suppressive microenvironment in IPF is an unexplored area that may lead to a paradigm shift in our understanding of the sequelae of exhaustion and immunosenescence, contributing to the identification of novel targets useful for therapeutic myeloid selection in IPF.
B7 antigen; bleomycin; CD28 antigen; endogenous compound; inducible T cell costimulator; transcription factor FOXP3; tumor necrosis factor; adult; CD8+ T lymphocyte; coculture; complication; conference abstract; controlled study; coronavirus disease 2019; cross-sectional study; down regulation; drug toxicity; exhaustion; female; fibrosing alveolitis; fluorescence activated cell sorting; follow up; human; human cell; human tissue; immunomodulation; immunosenescence; lung function; lymphocyte culture; major clinical study; male; microenvironment; monocyte; preliminary data; prospective study; regulatory T lymphocyte; resident; single cell RNA seq; suppressor cell; T lymphocyte; TCR signaling; transplant free survival
Full text:
Available
Collection:
Databases of international organizations
Database:
EMBASE
Type of study:
Prognostic study
Language:
English
Journal:
American Journal of Respiratory and Critical Care Medicine
Year:
2022
Document Type:
Article
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