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Project #12231
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#12231 : Identification of immune response signatures that correlate with therapeutic responses to TNF inhibitors using machine-learning algorithms
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Name of Applicant : Lars Rogge
Date of application : 16-09-2018
Unit : Immunoregulation
Location : Metchnikoff, 5th floor, Room 5022
Phone : 0140613822
@ Mail : lars.rogge@pasteur.fr

Project context and summary :

Anti-TNF therapy has revolutionized treatment of many chronic inflammatory diseases, including rheumatoid arthritis, Crohn’s disease and spondyloarthritis (SpA). However, clinical efficacy of TNF-inhibitors (TNFi) is limited by a high rate of non-responsiveness (30-40%) both in SpA and other diseases, exposing a substantial fraction of patients to important side-effects without any clinical benefit. Despite the extensive use of TNFi since many years, it is still not possible to determine which patients will respond to TNFi before treatment initiation. In this study, we have tested the hypothesis that the functional analysis of immune responses may not only improve our understanding of the molecular mechanisms of TNF-blocker activity, but also identify correlates of therapeutic responses in SpA patients. To facilitate the potential translation of our findings into a clinical setting, we have used standardized whole-blood stimulation assays (“TruCulture” assays, Duffy et al., Immunity 2014), and have minimized sources of pre-analytical variability, implementing a highly sensitive and robust pipeline to assess immune functions in patients. To investigate the concept that the immune status of a patient will define their response to TNFi treatment, we have used machine-learning algorithms to identify, in whole-blood stimulation assays, immunological transcripts that correlate with clinical efficacy of TNFi. Our results obtained with a cohort of 67 SpA patients demonstrate that high expression, before treatment initiation, of molecules associated with leukocyte invasion/migration and inflammatory processes predisposes to favorable outcome of anti-TNF therapy, while high-level expression of cytotoxic molecules was associated with poor therapeutic responses to TNF-blockers. These findings may suggest that SpA patients whose immune response is characterized by strong, NF-kB-mediated inflammation are more likely to benefit from TNFi treatment than patients with an active T/NK-cell component. Unfortunately our manuscript describing these results has been rejected by Nature Medicine. However, in her letter the editor mentioned, “Should future experimental data allow you to demonstrate that the identified gene signatures predict response to treatment and outperform previously reported approaches in an independent cohort, we would be happy to look at a new submission…”. We have recruited additional SpA patients over the summer and we are currently in the process of performing the gene expression analysis. The goal of this bioinformatic analysis will be to identify transcripts in stimulated immune cells that predict therapeutic outcome in a training set of patients using machine-learning algorithms and validate the findings in a replication cohort.


Related team publications :
IL-17 blockade with secukinumab in peripheral spondyloarthritis impacts synovial immunopathology without compromising systemic immune responses. van Mens LJJ, van de Sande MGH, Menegatti S, Chen S, Blijdorp ICJ, de Jong HM, Fluri IA, Latuhihin TE, van Kuijk AWR, Rogge L, Yeremenko NG, Baeten DLP. Arthritis Rheumatol. 2018 Jun 5. doi: 10.1002/art.40581. [Epub ahead of print] PMID: 29869838
Functional analysis via standardized whole-blood stimulation systems defines the boundaries of a healthy immune response to complex stimuli. Duffy D, Rouilly V, Libri V, Hasan M, Beitz B, David M, Urrutia A, Bisiaux A, Labrie ST, Dubois A, Boneca IG, Delval C, Thomas S, Rogge L, Schmolz M, Quintana-Murci L, Albert ML; Milieu Intérieur Consortium. Immunity. 2014 Mar 20;40(3):436-50. doi: 10.1016/j.immuni.2014.03.002. PMID: 24656047
Combinatorial control of Th17 and Th1 cell functions by genetic variations in genes associated with the interleukin-23 signaling pathway in spondyloarthritis. Coffre M, Roumier M, Rybczynska M, Sechet E, Law HK, Gossec L, Dougados M, Bianchi E, Rogge L. Arthritis Rheum. 2013 Jun;65(6):1510-21. doi: 10.1002/art.37936. PMID: 23508476
Service Delivery
Project Manager : vincent.guillemot@pasteur.fr
Project Type : Short
Status : In Progress


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