Combined Assessment of Immune Checkpoint Regulator VISTA on Tumor-Associated Immune Cells and Platelet-to-Lymphocyte Ratio Identifies Advanced Germ Cell Tumors with Higher Risk of Unfavorable Outcomes.

Abstract

Simple SummaryTesticular germ cell tumors (GCTs) are the most common malignancies in young males. The current treatment regimens are usually highly effective and curative. Nevertheless, a portion of patients presents with recurrence or succumbs due to the disease. There is an undoubtful necessity to investigate new prognostic markers to stratify the risk of such events. The current study aimed to evaluate the prognostic significance of markers of the tumor microenvironment and systemic inflammation markers in GCTs. We found that low expression of immune checkpoint proteins VISTA (V-domain Ig suppressor of T cell activation) and PD-L1 (programmed death-ligand 1) on tumor-associated immune cells and elevated inflammatory marker platelet-to-lymphocyte ratio are associated with a higher risk of events in testicular GCTs. It indicates a role of both local anti-tumor immune response and systemic inflammation in these tumors.In the current study, we aimed to investigate whether expression of immune checkpoint proteins (V-domain Ig suppressor of T cell activation (VISTA) and programmed death-ligand 1 (PD-L1)) and markers of systemic inflammation could predict progression/relapse and death in the cohort of 180 patients with testicular germ-cell tumors (GCTs). Expression of PD-L1 and VISTA was assessed by immunohistochemistry utilizing tissue microarrays. To estimate systemic inflammation neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) were calculated. We found high PD-L1 and VISTA expression on tumor-associated immune cells (TAICs) in 89 (49.44%) and 63 (37.22%) of GCTs, respectively, whereas tumor cells besides trophoblastic elements were almost uniformly negative. High PD-L1 was associated with seminomatous histology and lower stage. Relapses in stage I patients occurred predominantly in cases with low numbers of PD-L1 and VISTA-expressing TAICs. In stage II/III disease, the combination of low VISTA-expressing TAICs and high PLR was identified as predictor of shorter event-free survival (HR 4.10; 1.48–11.36, p = 0.006) and overall survival (HR 15.56, 95% CI 1.78–135.51, p = 0.001) independently of tumor histology and location of metastases. We demonstrated that the assessment of immune checkpoint proteins on TAICs may serve as a valuable prognostic factor in patients with high-risk testicular GCTs. Further study is warranted to explore the predictive utility of these biomarkers in GCTs.