For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
9
views
40
references
 Top references
cited by
7
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      265
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          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.

          Funding

          This work was supported by the Seerave Foundation and Dutch Cancer Society.

          Related collections

          Most cited references40

          • Record: found
          • Abstract: found
          • Article: not found

          PD-1 blockade induces responses by inhibiting adaptive immune resistance

          Paul Tumeh, Christina L. Harview, Jennifer Yearley … (2014)
          Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. 1–5 One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8 T-cells (termed adaptive immune resistance). 6,7 Here we show that pre-existing CD8 T-cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR). In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, and PD-L1 expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance.
          Article 0 comments Cited 1661 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

            James Larkin, Vanna Chiarion-Sileni, Rene Gonzalez … (2019)
            Article 0 comments Cited 1318 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade

              Mark Ayers, Jared Lunceford, Michael Nebozhyn … (2017)
              Programmed death-1–directed (PD-1–directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti–PD-1 therapies, including pembrolizumab. However, whether quantifying T cell–inflamed microenvironment is a useful pan-tumor determinant of PD-1–directed therapy response has not been rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients. We identified immune-related signatures correlating with clinical benefit using a learn-and-confirm paradigm based on data from different clinical studies of pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually defining a pan-tumor T cell–inflamed GEP in 220 patients with 9 cancers. Predictive value was independently confirmed and compared with that of PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell–inflamed GEP contained IFN-γ–responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for clinical benefit. The T cell–inflamed GEP has been developed into a clinical-grade assay that is currently being evaluated in ongoing pembrolizumab trials.
              Article 0 comments Cited 1317 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Veronique Bataille
                Mario Falchi
                Journal
                Journal ID (nlm-ta): eBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: eBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 22 August 2022
                Publication date Collection: September 2022
                Publication date (Electronic): 22 August 2022
                Volume: 83
                Electronic Location Identifier: 104235
                Affiliations
                [a ]Department of Twin Research and Genetic Epidemiology, King's College London, UK
                [b ]Centre for Inflammation Biology and Cancer Immunology, King's College London, UK
                [c ]Department CIBIO, University of Trento, Trento, Italy
                [d ]Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, the Netherlands
                [e ]Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
                [f ]Division of Haematology and Immunology, Institute of Medical Research at St James's, University of Leeds, UK
                [g ]Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK
                [h ]Department of Medical Oncology, Guy's and St Thomas’ NHS Foundation Trust, London, UK
                [i ]Liverpool Clatterbridge Cancer Centre, Liverpool, UK
                [j ]Department of Oncology, Lancashire Teaching Hospitals NHS Trust, Preston, UK
                [k ]The Christie NHS Foundation Trust, Manchester, UK
                [l ]Division of Cancer Sciences, University of Manchester, UK
                [m ]School of Cancer and Pharmaceutical Studies, King's College London, UK
                Author notes
                [* ]Corresponding author at: Department of Twin Research and Genetic Epidemiology, King's College London, UK. veronique.bataille@ 123456kcl.ac.uk
                [** ]Corresponding author. mario.falchi@ 123456kcl.ac.uk
                [1]

                Equal contribution.

                [2]

                Shared senior authorship.

                Article
                Publisher Item ID: S2352-3964(22)00417-0 Publisher ID: 104235
                DOI: 10.1016/j.ebiom.2022.104235
                PMC ID: 9421308
                PubMed ID: 36007304
                SO-VID: 13d6b6de-1779-4fe8-92c5-006246adc044
                Copyright © © 2022 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 11 March 2022
                Date revision received : 5 August 2022
                Date accepted : 5 August 2022
                Categories
                Subject: Articles

                Keywords: melanoma,checkpoint inhibitors,inflammatory proteins,response,survival
                Data availability:
                Keywords: melanoma, checkpoint inhibitors, inflammatory proteins, response, survival

                Comments

                Comment on this article

                scite_

                Similar content265

                See all similar

                Cited by7

                See all cited by

                Most referenced authors862

                See all reference authors