Profiling of inhibitory immune checkpoints in glioblastoma: Potential pathogenetic players

Abstract

Glioblastoma (GBM) represents the most frequent glial tumor, with almost 3 new cases per 100,000 people per year. Despite treatment, the prognosis for GBM patients remains extremely poor, with a median survival of 14.6 months, and a 5-year survival less than 5%. It is generally believed that GBM creates a highly immunosuppressive microenvironment, sustained by the expression of immune-regulatory factors, including inhibitory immune checkpoints, on both infiltrating cells and tumor cells. However, the trials assessing the efficacy of current immune checkpoint inhibitors in GBM are still disappointing. In the present study, the expression levels of several inhibitory immune checkpoints in GBM (CD276, VTCN1, CD47, PVR, TNFRSF14, CD200, LGALS9, NECTIN2 and CD48) were characterized in order to evaluate their potential as prognostic and eventually, therapeutic targets. Among the investigated immune checkpoints, TNFRSF14 and NECTIN2 were identified as the most promising targets in GBM. In particular, a higher TNFRSF14 expression was associated with worse overall survival and disease-free survival, and with a lower Th1 response.

Immunoglobulin‐like transcript 2 blockade restores antitumor immune responses in glioblastoma

“…Various studies have described the dysregulation of key inhibitory checkpoints and their ligands on glioblastoma, including HVEM or TIM‐3, among others. 35 , 36 In line with these results, in silico analysis revealed high expression of classical ( HLA‐A , ‐B , and ‐C ) and non‐classical ( HLA‐E and ‐F ) HLA‐I molecules in glioblastoma. Further, an important proportion of glioblastoma patients exhibited detectable levels of HLA‐A (90%) and HLA‐E (72.5%).…”

“…Indeed, tumor‐infiltrating lymphocytes isolated from patients with glioblastoma exhibit higher levels of numerous inhibitory checkpoints, such as PD‐1 and LAG3, compared to its counterparts from peripheral blood. 7 , 35 This evasion mechanism exploited by glioblastoma might be extendable to ILT2 because coculture with glioblastoma cells reduced NK cell‐mediated cytotoxicity and induced ILT2 upregulation on NK cells and CD8 + T cells. Therefore, ILT2 might work as an immune exhaustion marker in glioblastoma, similar to receptors such as PD‐1 or TIGIT.…”

“…Upregulation of inhibitory receptors on effector immune cells is a well‐known immune evasion strategy in cancer. Indeed, tumor‐infiltrating lymphocytes isolated from patients with glioblastoma exhibit higher levels of numerous inhibitory checkpoints, such as PD‐1 and LAG3, compared to its counterparts from peripheral blood 7,35 . This evasion mechanism exploited by glioblastoma might be extendable to ILT2 because coculture with glioblastoma cells reduced NK cell‐mediated cytotoxicity and induced ILT2 upregulation on NK cells and CD8 + T cells.…”

The anterior gradient homologue 2 (AGR2) co-localises with the glucose-regulated protein 78 (GRP78) in cancer stem cells, and is critical for the survival and drug resistance of recurrent glioblastoma: in situ and in vitro analyses

“…In addition, both cell lines indicated a high degree of migration in the scratch assay. A whole exome sequencing for Jed66_GB indicated the presence of TC-rare damaging COSMIC variants detected in genes that were previously associated with glioblastoma including BCR activator of RhoGEF and GTPase ( BCR ) [ 43 , 44 ], TNF receptor associated protein 1 ( TRAP1 ) [ 45 – 47 ], DNA polymerase delta 1, catalytic subunit ( POLD1 ) [ 48 ], otopetrin 1 ( OTOP1 ) [ 49 ], tyrosine kinase 2 ( TYK2 ) [ 50 ], AT-rich interaction domain 1B ( ARID1B ) [ 51 ], CD48 molecule ( CD48 ) [ 52 ], ubiquitin specific peptidase 18 ( USP18 ) [ 53 ], nuclear receptor corepressor 1 ( NCOR1 ) [ 54 ], NFE2 Like BZIP Transcription Factor 2 ( NFE2L2 ) [ 55 ], and Kinesin Family Member 1A ( KIF1A ) [ 56 ]. For Jed41_GB, exome sequencing showed the presence of TC-rare damaging COSMIC variants detected in glioblastoma-associated genes including TP53 [ 43 , 44 , 57 ], LDL receptor related protein 1B ( LRP1B ) [ 44 , 58 ], adhesion G protein-coupled receptor E5 ( ADGRE5 ) [ 59 ], atrophin 1 ( ATN1 ) [ 60 ], autophagy related 2B ( ATG2B ) [ 61 , 62 ], MYC associated zinc finger protein ( MAZ ) [ 23 , 63 ], WNK lysine deficient protein kinase 1 ( WNK1 ) [ 64 , 65 ], UDP glucuronosyltransferase family 1 member A1 ( UGT1A1 ) [ 66 ], and UDP glucuronosyltransferase family 1 member A6 ( UGT1A6 ) [ 67 ].…”

Radiation-Triggered Selenium-Engineered Mesoporous Silica Nanocapsules for RNAi Therapy in Radiotherapy-Resistant Glioblastoma

“…Glioblastoma multiforme (GBM, WHO IV), a lethal primary brain malignancy, is characterized by extensive infiltration, high recurrence, and a low 5-year survival rate (<5%). , High-energy ionizing radiation therapy (RT) to induce tumor ablation is the contemporary standard of care for GBM after maximal safe surgical resection. − Unfortunately, low-dose therapeutic RT modalities for GBM remain dismal and are largely restricted by radiation resistance with strong diffuse infiltration and DNA repair response …”