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

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.

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

“…Local tumor microenvironment and systemic immune or inflammatory response seem to influence each other in cancer patients [ 38 ]. Xiang et al demonstrated that high NLR was associated with worse OS and decreased CD8 + /CD28 − and CD4 + /CD25 + cell subsets in pancreatic cancer settings [ 39 ].…”

Detection of Specific Immune Cell Subpopulation Changes Associated with Systemic Immune Inflammation–Index Level in Germ Cell Tumors

“…Inflammation is implicated in several aspects of cancer biology, including cancer development, progression and prognosis [ 5 , 35 , 36 ]. The malignant process influences the host immune system not only at the tumor site but also on a global level by forming a systemic inflammatory response [ 37 ]. An impaired intratumoral inflammatory response and an elevated systemic response suggests decreased immunological control of tumors at the local level, whereas the formation of a systemic pro-inflammatory environment creates suitable conditions for cancer progression [ 38 , 39 ].…”

Comprehensive Assessment of Selected Immune Cell Subpopulations Changes in Chemotherapy-Naïve Germ Cell Tumor Patients

“…Several systemic inflammatory markers that are easily obtained from routine blood tests, such as leukocyte, neutrophil and thrombocyte counts, have been proposed as potentially additional predictive and prognostic markers that can be used in various malignancies. In recent years, several reports established the prognostic and the predictive role of inflammatory indices, such as the neutrophil-to-lymphocyte ratio (23)(24)(25)(26)(27)(28), platelet-to-lymphocyte ratio (28,29) and the systemic immune-inflammation index (SII) (24,28,30) in testicular GCTs. All these data emphasized the important role of the immune response in GCTs (29).…”

“…In recent years, several reports established the prognostic and the predictive role of inflammatory indices, such as the neutrophil-to-lymphocyte ratio (23)(24)(25)(26)(27)(28), platelet-to-lymphocyte ratio (28,29) and the systemic immune-inflammation index (SII) (24,28,30) in testicular GCTs. All these data emphasized the important role of the immune response in GCTs (29). Therefore, there is an evident need to address the influence of the immunological response on the development of GCTs, as well as on the outcome of GCT patients.…”