TIGIT and PD-1 Immune Checkpoint Pathways Are Associated With Patient Outcome and Anti-Tumor Immunity in Glioblastoma.

Itay Raphael,Ian F Pollack,Frank S Lieberman,Aaron A Diaz,Lin Wang,Tullia C Bruno,Poorva Sandlesh,Rajeev Kumar,Alexandra Foster,Baoli Hu,Gary Kohanbash,Marissa Lynn Campagna,Jordan Allen,Shuyan Zhai,Dhivyaa Rajasundaram,Alberto Broniscer,Sameer Agnihotri,Chaim T Sneiderman ,Karsen E Shoger ,Brandyn Castro ,Lauren Mccarl ,Nduka Amankulor

doi:10.3389/fimmu.2021.637146

Abstract

Glioblastoma (GBM) remains an aggressive brain tumor with a high rate of mortality. Immune checkpoint (IC) molecules are expressed on tumor infiltrating lymphocytes (TILs) and promote T cell exhaustion upon binding to IC ligands expressed by the tumor cells. Interfering with IC pathways with immunotherapy has promoted reactivation of anti-tumor immunity and led to success in several malignancies. However, IC inhibitors have achieved limited success in GBM patients, suggesting that other checkpoint molecules may be involved with suppressing TIL responses. Numerous IC pathways have been described, with current testing of inhibitors underway in multiple clinical trials. Identification of the most promising checkpoint pathways may be useful to guide the future trials for GBM. Here, we analyzed the The Cancer Genome Atlas (TCGA) transcriptomic database and identified PD1 and TIGIT as top putative targets for GBM immunotherapy. Additionally, dual blockade of PD1 and TIGIT improved survival and augmented CD8+ TIL accumulation and functions in a murine GBM model compared with either single agent alone. Furthermore, we demonstrated that this combination immunotherapy affected granulocytic/polymorphonuclear (PMN) myeloid derived suppressor cells (MDSCs) but not monocytic (Mo) MDSCs in in our murine gliomas. Importantly, we showed that suppressive myeloid cells express PD1, PD-L1, and TIGIT-ligands in human GBM tissue, and demonstrated that antigen specific T cell proliferation that is inhibited by immunosuppressive myeloid cells can be restored by TIGIT/PD1 blockade. Our data provide new insights into mechanisms of GBM αPD1/αTIGIT immunotherapy.

Highlights

Malignant gliomas are the most common primary malignant central nervous system (CNS) tumor in adults [1]
To identify putative immunotherapy targets for GBM, we evaluated the expression of Immune checkpoint (IC) genes and their ligands in RNA
Expression of genes for CD155 (PVR), PD-L1, and ICOS-L, the ligands for TIGIT, PD1, and ICOS, respectively, was significantly associated with decreased overall survival (OS) and disease-free survival (DFS), whereas upregulated expression of other IC gene ligands did not affect these parameters in GBM patients (Figures 2A, B)

Summary

Introduction

Malignant gliomas are the most common primary malignant central nervous system (CNS) tumor in adults [1]. Glioblastoma (GBM) are highly aggressive brain cancers and the most common type of high-grade glioma (HGG) [2]. The current standard of care for GBM patients include a combination of surgery, radiation therapy, and chemotherapy. The development of immunoregulatory drugs that block IC pathways, such as PD1/ PD-L1 inhibitors, have emerged as a promising treatment strategy against a variety of malignancies, including melanoma, lung cancers, and head and neck cancers [9, 10]. AntiPD1/PD-L1 immunotherapy shows durable response in other types of malignancies, its efficacy is limited to approximately 10% of GBM patients [11,12,13], highlighting the need for more effective and novel approaches, including the combination of additional IC inhibitors (ICIs) to target several IC pathways simultaneously

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Conclusion