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

doi:10.1016/j.ebiom.2022.104235

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

EBioMedicine. 2022 Sep:83:104235. doi: 10.1016/j.ebiom.2022.104235. Epub 2022 Aug 22.

Authors

Niccolò Rossi¹, Karla A Lee¹, Maria V Bermudez², Alessia Visconti¹, Andrew Maltez Thomas³, Laura A Bolte⁴, Johannes R Björk⁴, Laura Kist de Ruijter⁵, Julia Newton-Bishop⁶, Mark Harland⁶, Heather M Shaw⁷, Mark Harries⁸, Joseph Sacco⁹, Ruth Board¹⁰, Paul Lorigan¹¹, Elisabeth G E de Vries⁵, Nicola Segata³, Leonie Taams², Sophie Papa¹², Tim D Spector¹, Paul Nathan⁷, Rinse K Weersma⁴, Geke A P Hospers⁵, Rudolf S N Fehrmann⁵, Veronique Bataille¹³, Mario Falchi¹⁴

Affiliations

¹ Department of Twin Research and Genetic Epidemiology, King's College London, UK.
² Centre for Inflammation Biology and Cancer Immunology, King's College London, UK.
³ Department CIBIO, University of Trento, Trento, Italy.
⁴ Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, the Netherlands.
⁵ Department of Medical Oncology, University of Groningen, University Medical Center Groningen, the Netherlands.
⁶ Division of Haematology and Immunology, Institute of Medical Research at St James's, University of Leeds, UK.
⁷ Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK.
⁸ Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁹ Liverpool Clatterbridge Cancer Centre, Liverpool, UK.
¹⁰ Department of Oncology, Lancashire Teaching Hospitals NHS Trust, Preston, UK.
¹¹ The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, UK.
¹² 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.
¹³ Department of Twin Research and Genetic Epidemiology, King's College London, UK; Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK. Electronic address: veronique.bataille@kcl.ac.uk.
¹⁴ Department of Twin Research and Genetic Epidemiology, King's College London, UK. Electronic address: mario.falchi@kcl.ac.uk.

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.

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

Keywords: Checkpoint inhibitors; Inflammatory proteins; Melanoma; Response; Survival.

Publication types

Meta-Analysis

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Chemokine CCL8
Hepatocyte Growth Factor
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Inflammation / drug therapy
Interleukin-6
Ipilimumab / therapeutic use
Melanoma* / pathology
Nivolumab
Skin Neoplasms* / drug therapy
Skin Neoplasms* / pathology

Substances

Chemokine CCL8
Immune Checkpoint Inhibitors
Interleukin-6
Ipilimumab
Nivolumab
Hepatocyte Growth Factor

Grants and funding

MR/M019012/1/MRC_/Medical Research Council/United Kingdom