RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

Abstract

Introduction: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM). Methods: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG). Results: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p=0.003), CD137 (p=0.042), VEGF-A (p<0.001), CTLA4 (p=0.028), CD40 (p=0.023), GITR (p=0.020), IL6 (p=0.02), and OX40 (p<0.001). In CGCG (n=52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant. Conclusions: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

OX40 and OX40L protein expression of tumor infiltrating lymphocytes in non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers

“…To our knowledge, it is the first research to analyze the role of OX40/OX40L in early-stage resectable NSCLC and demonstrate its relationships with PD-1/PD-L1, TILs and patients' clinical outcomes. OX40/OX40L has already been studied previously as an immune characteristic biomarker in some other cancer types, including lymphoma, hepatocellular carcinoma, Leukemia, ovarian, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer and breast cancer (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). The TILs OX40 was reported to correlate with patient survival.…”

Gene expression profiling identified TP53MutPIK3CAWild as a potential biomarker for patients with triple‑negative breast cancer treated with immune checkpoint inhibitors

“…To this end, CYT, a surrogate measurement of the magnitude of the cytolytic immune response was used (31). CYT was calculated as the geometric mean of GZMA and PRF1 expression, and has served as a highly specific marker in human glioblastoma (32). Based on this index, a very weak correlation was observed between the TMB and CYT in patients with TNBC ( Fig.…”