Type, Frequency, and Spatial Distribution of Immune Cell Infiltrates in CNS Germinomas: Evidence for Inflammatory and Immunosuppressive Mechanisms

Abstract

Central nervous system germinomas are characterized by a massive immune cell infiltrate. We systematically characterized these immune cells in 28 germinomas by immunophenotyping and image analysis. mRNA expression was analyzed by Nanostring technology and in situ RNA hybridization. Tumor infiltrating lymphocytes (TILs) were composed of 61.8% ± 3.1% (mean ± SE) CD3-positive T cells, including 45.2% ± 3.5% of CD4-positive T-helper cells, 23.4% ± 1.5% of CD8-positive cytotoxic T cells, 5.5% ± 0.9% of FoxP3-positive regulatory T cells, and 11.9% ±1.3% PD-1-positive TILs. B cells accounted for 35.8% ± 2.9% of TILs and plasma cells for 9.3% ± 1.6%. Tumor-associated macrophages consisted of clusters of activated PD-L1-positive macrophages and interspersed anti-inflammatory macrophages expressing CD163. Germinoma cells did not express PD-L1. Expression of genes encoding immune cell markers and cytokines was high and comparable to mRNA levels in lymph node tissue. IFNG and IL10 mRNA was detected in subfractions of TILs and in PD-L1-positive macrophages. Taken together, the strong immune reaction observed in germinomas involves inflammatory as well as various suppressive mechanisms. Expression of PD-1 and PD-L1 and infiltration of cytotoxic T cells are biomarkers predictive of response to anti-PD-1/PD-L1 therapies, constituting a rationale for possible novel treatment approaches.

Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance

“…In this study, however, we found the immune cell types adjacent to tumour cells were far more varied (Figure C ). This result is in line with the recent findings from an immunohistochemistry examination of the germinoma microenvironment, which revealed the presence of a wide variety of immune cells, where B and T cells were predominant .…”

Diagnostic radiation-induced regression of a metastatic primary intracranial germinoma: a case report

“…The number of TILs could be so numerous as to obscure the underlying tumor cells and, as exhibited by our case's first biopsy specimen, can pose diagnostic challenges. 19 The prescription of potent glucocorticoids can theoretically reduce tumor mass, but since only maintenance hydrocortisone was administered for our patient's hypopituitaric hypocortisolism we believe this was unlikely to be the underlying mechanism. 6,7,20 Furthermore, a review of 153 patients with histologically proven germ cell tumors that were prescribed at least 280mg of postoperative prednisolone did not detect a single case of tumor shrinkage before definitive onco-logic therapy.…”

“…23 But recent immunophenotyping and mRNA expression analyses have elucidated the dual role of TILs in both suppressing and promoting germinoma cell growth. 19 Therefore given the current lack of understanding of the complex interplay between immune and tumor cells drawing definitive conclusions on the hypothesis of immune-mediated tumor regression may be premature.…”

Gender Related Changes in Gene Expression Induced by Valproic Acid in A Mouse Model of Autism and the Correction by S-adenosyl Methionine. Does It Explain the Gender Differences in Autistic Like Behavior?

“…NanoString assay is reported to be reliable, high-throughput assay used to simultaneously screen for gene expression changes in clinical practice [127,128]. Studies that used the NanoString n-counter system usually did not use rtPCR analysis for validation [129,130,131,132].…”