Are Changes in the Percentage of Specific Leukocyte Subpopulations Associated with Endogenous DNA Damage Levels in Testicular Cancer Patients?

Katarina Kalavska,Michal Chovanec,Jana Obertova,Jozef Mardiak,Lenka Hurbanova,Daniela Svetlovska,Viera Miskovska,Katarína Kozics,Andrea Mlcakova,Zuzana Sycova-Mila,Zuzana Sestakova,Katarina Rejlekova,Paulina Gronesova,Patrik Palacka,Miroslav Chovanec,Michal Mego

doi:10.3390/ijms22158281

Abstract

Chemoresistance of germ cell tumors (GCTs) represents an intensively studied property of GCTs that is the result of a complicated multifactorial process. One of the driving factors in this process is the tumor microenvironment (TME). Intensive crosstalk between the DNA damage/DNA repair pathways and the TME has already been reported. This study aimed at evaluating the interplay between the immune TME and endogenous DNA damage levels in GCT patients. A cocultivation system consisting of peripheral blood mononuclear cells (PBMCs) from healthy donors and GCT cell lines was used in an in vitro study. The patient cohort included 74 chemotherapy-naïve GCT patients. Endogenous DNA damage levels were measured by comet assay. Immunophenotyping of leukocyte subpopulations was performed using flow cytometry. Statistical analysis included data assessing immunophenotypes, DNA damage levels and clinicopathological characteristics of enrolled patients. The DNA damage level in PBMCs cocultivated with cisplatin (CDDP)-resistant GCT cell lines was significantly higher than in PBMCs cocultivated with their sensitive counterparts. In GCT patients, endogenous DNA damage levels above the cutoff value were independently associated with increased percentages of natural killer cells, CD16-positive dendritic cells and regulatory T cells. The crosstalk between the endogenous DNA damage level and specific changes in the immune TME reflected in the blood of GCT patients was revealed. The obtained data contribute to a deeper understanding of ongoing interactions in the TME of GCTs.

Highlights

Germ cell tumors (GCTs) are the most common solid malignancy among young men aged 14–44 years
Applying the 2D coculture model, we have achieved interesting results showing that the DNA damage level in peripheral blood mononuclear cells (PBMCs) cocultivated with cisplatin (CDDP)-resistant germ cell tumors (GCTs) cell lines is significantly higher than in PBMCs cocultivated with their sensitive counterparts after 120 h of cocultivation
We show that PBMCs cocultivated with GCT cell lines resistant to CDDP demonstrate elevated levels of endogenous DNA damage compared to those observed in PBMCs cocultivated with their CDDP-sensitive parental GCT cell lines

Summary

Introduction

Germ cell tumors (GCTs) are the most common solid malignancy among young men aged 14–44 years. Despite the exceptional treatment effect of the combination of surgery and cisplatin (CDDP)-based chemotherapy, there is a subgroup of patients (approximately 10–15%) who become refractory to therapy or experience disease relapse. The chemoresistance of GCT is a complex and multifactorial phenomenon that is closely associated with the tumor microenvironment (TME) [4]. At present, published data indicate that GCTs are richly infiltrated by immune cells that modulate the TME in multiple ways, including cytokine secretion. Siska and colleagues provided interesting data characterizing T cell subsets and immune checkpoints in the immune infiltrate in testicular

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