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Circulating IL-6 is associated with disease progression in BRAFwt metastatic melanoma patients receiving anti-PD-1 therapy
  1. Katarina Mirjačić Martinović1,
  2. Ana Vuletić1,
  3. Nevena Tišma Miletić1,
  4. Suzana Matković2,
  5. Dušica Gavrilović3,
  6. Aleksandra Ninković4,
  7. Vladimir Jurišić5,
  8. Nada Babović2
  1. 1 Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, Belgrade, Serbia
  2. 2 Department of Medical Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, Belgrade, Serbia
  3. 3 Data Centre, Institute of Oncology and Radiology of Serbia, Pasterova 14, Belgrade, Serbia
  4. 4 Department of Biochemistry, Institute of Oncology and Radiology of Serbia, Pasterova 14, Belgrade, Serbia
  5. 5 Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
  1. Correspondence to Dr Katarina Mirjačić Martinović, Institute of Oncology and Radiology of Serbia, Beograd, Serbia; katarina.mirjacic{at}ncrc.ac.rs

Abstract

Aims Despite efficacy of anti-PD-1 blockade in treatment of metastatic melanoma (MM), many patients achieve rapid disease progression (DP). Therefore, the aim of this study is to better define biomarkers for DP by analysing levels of circulating cytokines TGF-β, IFN-γ, IL-6, IL-8 and IL-10 in MM patients prior to anti-PD-1 therapy.

Methods Cytokine levels were evaluated before therapy with pembrolizumab in peripheral blood of BRAF wild-type (wt) MM patients by ELISA method.

Results In this study, we give pretherapy levels for circulating TGF-β, IFN-γ, IL-6, IL-8 and IL-10 in BRAFwt MM patients and analyse them according to metastasis stage (M1a+M1 b, M1c, M1d groups), lactate dehydrogenase (LDH) level and occurrence of DP. Increased IL-6 level was found in M1d group (central nervous system metastasis), while LDH+patients (LDH ≥460 IU/L) have increased IL-6 and IL-8 values that correlate with LDH level. Also, IL-6 correlates with C reactive protein values. Furthermore, patients with DP have significantly higher IL-6 level compared with non-DP patients. Conversely, the other analysed cytokines are similar in investigated groups of MM patients. By receiver operating characteristics curve analysis, pretherapy IL-6 level was found to be a biomarker for the occurrence of DP with cut-off value of 3.02 pg/mL. Patients in M1d stage are prevalent in the group with IL-6 ≥3.02 pg/mL that is characterised with reduced progression-free survival and higher pretherapy IL-8 and LDH.

Conclusion The evidence in this study implies that baseline IL-6 could be a biomarker of DP and poor prognosis in BRAFwt MM patients treated with pembrolizumab.

  • Biomarkers, Tumor
  • CYTOKINES
  • MELANOMA

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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Footnotes

  • Handling editor Vikram Deshpande.

  • Contributors KMM is the guarantor of the study. KMM, AV, NTM and VJ conceived the idea of the study. All authors contributed to the design of the research. NB and SM were involved in data collection. KMM, AV and NTM performed ELISA assays, AN performed CRP measurements, while DG was engaged in statistical analysis. All authors approved the final version of the manuscript.

  • Funding This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (451-03-68/2022-14/200043 and 175056).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.