Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy
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Monoclonal antibodies targeting immune checkpoints are gaining ground in the treatment of melanoma and other cancers, and considerable effort is made to identify biomarkers predicting the efficacy of these therapies. Our retrospective study was performed on surgical tissue samples (52 lymph nodes and 34 cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma treated with ipilimumab. Using a panel of 11 antibodies against different immune cell types, intratumoral immune cell densities were determined and evaluated in relation to response to ipilimumab treatment and disease outcome. For most markers studied, median immune cell densities were at least two times higher in lymph node metastases compared to skin/subcutaneous ones; therefore, the prognostic and predictive associations of immune cell infiltration were evaluated separately in the two groups of metastases as well as in all samples as a whole. Higher prevalence of several immune cell types was seen in lymph node metastases of the responders compared to non-responders, particularly FOXP3+ cells and CD8+ T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand, significant difference could be observed only in the case of CD16 and CD68. Associations of labeled cell densities with survival were also found for most cell types studied in nodal metastases, and for CD16+ and CD68+ cells in skin/s.c. metastatic cases. Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.
KeywordsMelanoma Immunotherapy Ipilimumab Biomarker Tumor-infiltrating immune cells
Antibody-dependent cellular cytotoxicity
Eastern cooperative oncology group
New York esophageal squamous cell carcinoma-1
Vascular endothelial growth factor
The authors thank Katalin Derecskei and Miklós Kónya (National Institute of Oncology, Budapest) for their excellent technical assistance.
Compliance with ethical standards
The study was supported by the National Research, Development and Innovation Office Grants NKFI K105132, K116295, and by European Union GINOP_2.3.2-15-2016-00020.
Conflict of interest
Tímea Balatoni has received speaker honoraria and financial support for attending symposia from Bristol-Myers Squibb, MSD Sharp and Dohme (MSD), Novartis, and Roche. Gabriella Liszkay is on the advisory board and has received honoraria for speaking at conferences as well as financial support for educational programs from Bristol-Myers Squibb, GlaxoSmithKline, MSD, Novartis, and Roche. Judit Oláh has acted as a speaker of symposia and consultant for Bristol-Myers Squibb, MSD, Novartis and Roche. Zsuzsanna Lengyel has received speaker honoraria from Bristol-Myers Squibb, MSD, Novartis, and Roche. Gabriella Emri has received speaker honoraria from Bristol-Myers Squibb, MSD, and Roche. All other authors declare that they have no conflict of interest.
Ethical approval and ethical standards
The study followed the Declaration of Helsinki and was approved by the Scientific and Ethical Committee of Medical Research Council, Hungary (2506-3/2017/EKU). Informed consents from patients were not required by the board in case of retrospective studies where it is not possible to obtain consents from the majority of patients as in this case where most patients were deceased at the time of the study.
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