Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma
Niccolò Rossi,
Karla A. Lee,
Maria V. Bermudez,
Alessia Visconti,
Andrew Maltez Thomas,
Laura A. Bolte,
Johannes R. Björk,
Laura Kist de Ruijter,
Julia Newton-Bishop,
Mark Harland,
Heather M. Shaw,
Mark Harries,
Joseph Sacco,
Ruth Board,
Paul Lorigan,
Elisabeth G.E. de Vries,
Nicola Segata,
Leonie Taams,
Sophie Papa,
Tim D. Spector,
Paul Nathan,
Rinse K. Weersma,
Geke A.P. Hospers,
Rudolf S.N. Fehrmann,
Veronique Bataille,
Mario Falchi
Affiliations
Niccolò Rossi
Department of Twin Research and Genetic Epidemiology, King's College London, UK
Karla A. Lee
Department of Twin Research and Genetic Epidemiology, King's College London, UK
Maria V. Bermudez
Centre for Inflammation Biology and Cancer Immunology, King's College London, UK
Alessia Visconti
Department of Twin Research and Genetic Epidemiology, King's College London, UK
Andrew Maltez Thomas
Department CIBIO, University of Trento, Trento, Italy
Laura A. Bolte
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, the Netherlands
Johannes R. Björk
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, the Netherlands
Laura Kist de Ruijter
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
Julia Newton-Bishop
Division of Haematology and Immunology, Institute of Medical Research at St James's, University of Leeds, UK
Mark Harland
Division of Haematology and Immunology, Institute of Medical Research at St James's, University of Leeds, UK
Heather M. Shaw
Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK
Mark Harries
Department of Medical Oncology, Guy's and St Thomas’ NHS Foundation Trust, London, UK
Joseph Sacco
Liverpool Clatterbridge Cancer Centre, Liverpool, UK
Ruth Board
Department of Oncology, Lancashire Teaching Hospitals NHS Trust, Preston, UK
Paul Lorigan
The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, UK
Elisabeth G.E. de Vries
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
Nicola Segata
Department CIBIO, University of Trento, Trento, Italy
Leonie Taams
Centre for Inflammation Biology and Cancer Immunology, King's College London, UK
Sophie Papa
Department of Medical Oncology, Guy's and St Thomas’ NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Studies, King's College London, UK
Tim D. Spector
Department of Twin Research and Genetic Epidemiology, King's College London, UK
Paul Nathan
Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK
Rinse K. Weersma
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, the Netherlands
Geke A.P. Hospers
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
Rudolf S.N. Fehrmann
Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands
Veronique Bataille
Department of Twin Research and Genetic Epidemiology, King's College London, UK; Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK; Corresponding author at: Department of Twin Research and Genetic Epidemiology, King's College London, UK.
Mario Falchi
Department of Twin Research and Genetic Epidemiology, King's College London, UK; Corresponding author.
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.
