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    Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma

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    Authors
    Rossi, N.
    Lee, K. A.
    Bermudez, M. V.
    Visconti, A.
    Thomas, A. M.
    Bolte, L. A.
    Björk, J. R.
    de Ruijter, L. K.
    Newton-Bishop, J.
    Harland, M.
    Shaw, H. M.
    Harries, M.
    Sacco, J.
    Board, R.
    Lorigan, Paul C
    de Vries, E. G. E.
    Segata, N.
    Taams, L.
    Papa, S.
    Spector, T. D.
    Nathan, P.
    Weersma, R. K.
    Hospers, G. A. P.
    Fehrmann, R. S. N.
    Bataille, V.
    Falchi, M.
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    Affiliation
    Department of Twin Research and Genetic Epidemiology, King's College London, UK
    Issue Date
    2022
    
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    Abstract
    Background: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma. Methods: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival. Findings: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10-4, 2.29 × 10-4, and 1.02 × 10-3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10-2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10-3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response. Interpretation: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy.
    Citation
    Rossi N, Lee KA, Bermudez MV, Visconti A, Thomas AM, Bolte LA, et al. Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma. EBioMedicine. 2022 Sep;83:104235. PubMed PMID: 36007304. Pubmed Central PMCID: PMC9421308. Epub 2022/08/26. eng.
    Journal
    EBioMedicine
    URI
    http://hdl.handle.net/10541/625600
    DOI
    10.1016/j.ebiom.2022.104235
    PubMed ID
    36007304
    Additional Links
    https://dx.doi.org/10.1016/j.ebiom.2022.104235
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ebiom.2022.104235
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