Objective Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost–benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value.
Design We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution—meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts.
Results We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) –axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%.
Conclusions Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.
- gene expression
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RG, ES and NM contributed equally.
YC, PK and SSS-O contributed equally.
Contributors RG, FV, ESt, NM,SP, PK, YC and SSS-O designed the research; RG, ESt, NM, FV and ESa analysed the data; ESt, NM, ESa and SP performed the experiments; HB-Y, SP, RW, IG, MW,KR, HY, ID, ESa and YC contributed to clinical part; RG, ESt, NM, FV, PK, YC and SSS-O wrote the manuscript.
Funding This work was supported by funding of the Helmsley Charitable Trust to YC, SSS-O and ID. PK is funded by the NIH’NIAID (grants U19AI109662, U 19AI057229, and U54I117925) and the Bill and Melinda Gates Foundation. FV by NIH K12 fellowship #5K12HL120001-02, RG was funded by the Lady Davis postdoctoral fellowship and by NIH’NIAID U19AI090019.
Competing interests YC declares Abbvie grant support, advisory and lecture fees, Janssen advisory and lecture fees, Takeda grant support and advisory and lecture fees, Pfizer advisory and lecture fees and Protalix Advisory fees. RG and ESt declares CytoReason equity and advisory fees. RG declares equity in CytoReason. SSO-O declares CytoReason equity and advisory fees and Takeda grant support.
Patient consent Obtained.
Ethics approval RAMBAM hospital IRB, Ichilov hospital IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
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