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

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.

Myeloid-derived suppressor cells in hematologic malignancies: two sides of the same coin

“…Tumor-derived MDSCs activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor kappa B (NF-κB) signaling pathway in PD-1 - PD-L1 + Bregs via the PD-1/PD-L1 axis, which mediates their immunosuppressive function [ 62 ]. MDSCs have also been found to express PD-1, PD-L1, and T-cell immunoglobulin and ITIM structural domain protein (TIGIT) ligands in human glioma tissues, thereby blocking TIGIT/PD1 to restore T-cell proliferation and immune function [ 63 ].…”

TIGIT Is Positively Associated with Advanced Human Glioma and Displays an Immunosuppressive Microenvironment

“…Several studies explored the role of TIGIT in different cancer sites such as bladder, colorectal, melanoma and blood [13,15,16,40]. TIGIT was also explored to show difference in expression between GBM and Multiple Sclerosis [41], and as a potential therapeutic target upon a dual blockade of anti-TIGIT with anti-PD-1 in a murine GBM model [21,42]. At the best of our knowledge, our study is the first one to assess the role of TIGIT in the progression of human glioma.…”

Novel Immune Checkpoints in Esophageal Cancer: From Biomarkers to Therapeutic Targets

“…In Italy, Raphael et al. ( 135 ) described that IC pathways TIGIT and PD-1 are associated with patient outcome and antitumor immunity in glioblastoma.…”