Introduction: Immunomodulation and tumor induced tolerance is one of the central mechanisms in the oncogenesis of malignant and benign neoplasms. While numerous pathways have been described, signaling through the Programmed Death 1 receptor (PD-1) on T lymphocytes, via activation through its ligand, Programmed Death 1 Ligand (PD-L1) is one of the central pathways involved in tumor induced tolerance. Germinomas of the central nervous system (CNS) have been classically characterized as a “Two Cell” tumor with histologic analysis exhibiting an abundance of quiescent tumor infiltrating lymphocytes. We therefore investigated whether PD-L1 expression may be responsible for germinoma induced T cell anergy, and if these tumors may be susceptible to immunotherapy.
Methods: Pathologic specimens obtained from 22 cases of CNS germinomas between 2000 and 2016 were analyzed for the presence of PD-L1 and PD1 expression by immunohistochemistry. 1.5mm core sections from each tumor was stained with antibodies directed toward PD-L1 (SP142, Ventana Benchmark; SP142, Leica Bond) and PD-1 (NAT105, Leica/Abcam). OCT3/4 staining was used to confirm germ cell tumor localization.
Results: 19 of 22 (86%) germinomas harbored germ cell components that stained positively for PD-L1. Positive lymphocyte staining for PD-L1 was evident in 16 cases. PD-1 expression was relegated to lymphocytes, as expected.
Conclusions: PD-L1 expression is detectable in the majority of sampled germinomas and may contribute to lymphocyte quiescence observed in these tumors. These results raise the possibility that immune checkpoint inhibitors may have a therapeutic role in future treatment of germinomas.
Patient Care: Germinomas represent germ cell derived tumors that are found within the pineal and suprasellar region within the central nervous system. CNS Germinomas represent approximately 3-5% of all pediatric brain tumors and generally present with local mass effect inducing hydrocephalus and Parinaud’s Syndrome. Classically, Germinomas have been shown to be radiosensitive and the optimal management for CNS Germinomas has included craniospinal radiation with additional boost radiation to the tumor bed. In one large cohort using standard radiation strategies, the 5 year overall survival for patients with CNS germinomas was 93% with a 5 year median progression free survival. Despite reassuring clinical outcomes using traditional treatment algorithms, much controversy exists around the optimal management of germinomas as significant morbidity does exist with standard radiation regimens. Additionally, as germinomas generally present in adolescents there is increasing attention paid to long term outcomes and long term disease and treatment morbidity. As such, understanding the tumorgenesis of these rare pediatric tumors is imperative. This work identifies that a high percentage of germinomas express PD-L1 thereby potentially explaining the quiescent lymphocytic infiltrate which has long been observed in these tumors. This work further suggests that germinomas may be sensitive to checkpoint inhibitors targeting PD-L1. This may be a particularly useful treatment strategy in instances where germinomas recur or progress despite standard radiation therapy.
Learning Objectives: By the end of this session, participants should be able to:
1) Explain the mechanism of PD-L1 mediated tumor induced tolerance
2) Describe the histologic features of CNS germinomas
3) Describe how immune checkpoint inhibitors such as nivolumab may be useful in the treatment of CNS germinomas
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