High Grade Glioma (HGG) is the most common adult CNS tumor and known by its high tumor mutation load (TML). Mismatch repair protein (MMR) is a set of proteins (namely MLH1 and MSH2) that are responsible to maintain genomic integrity. Loss of MMR expressions or Mismatch Repair Deficiency (MMRD) may lead to TML inducing production of neoantigens and iliciting cellular immune responses. Programmed death-ligand 1 (PD-L1) is widely known as co-inhibitory ligand which is responsible for immune evasion by tumor cells. The interaction among MMRD, PD-L1 and apoptotic factor, TP53, in HGG has been subjects of our investigation within patient cohort treated in Indonesian private hospital.
We performed Immunohistochemistry (IHC) assays on 43 High Grade Glioma FFPE samples from Siloam Hospital. The assay were optimized to detect MLH1, MSH2, TP53 and PD-L1 protein expression. E1L3N antibody was used to detect PD-L1 expression. MMR deficient was defined as loss of at least one of MMR proteins (MLH1, MSH) expressions. Statistical analysis were used to describe association among biomarkers as well as the age group and histological classification [Glioblastoma Multiforme (GBM) vs Other HGG (Non-GBM)].
Four sample which not qualified were omitted from analysis. MMRD were found in 33% patient (13/39) and was associated with negative expression of TP53 (p = 0.0161), suggesting TP53 independent pathway of genetic instability. PD-L1 positive rate tend to be higher in MMRD (38%) than MMR proficient (MMRP 11%) cohorts, albeit not statistically significant (p = 0.0896). There is no significant relationship between MMRD and age group as well as histological status. Overall survival analyses showed MMRD was associated with poor prognosis (p = 0.005).
MMRD may serve as useful prognostic biomarker predicting patients with poor survival. Moreover, a subset of patients with MMRD may express PD-L1 protein, a prominent predictive biomarker for immune checkpoint therapy.
Clinical trial identification
Legal entity responsible for the study
Universitas Pelita Harapan Faculty of Medicine
Kalbe Farma Tbk
All authors have declared no conflicts of interest.