Abstract
Simple SummaryBiomarkers for predicting the response to immune checkpoint blockade (ICB) includes programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC), microsatellite instability (MSI), and tumor mutation burden (TMB). This study investigated the relationship of these biomarkers using comprehensive cancer panel assay (CCPA) with >500 genes in 588 advanced cancer patients. The work demonstrates that PD-L1 expression is significantly associated with TMB and MSI score, according to primary tumor origin.Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC), microsatellite instability (MSI), and tumor mutation burden (TMB) have been proposed as a predictive biomarker to predict response to immune checkpoint blockade (ICB). We aimed to find the relationship of PD-L1 IHC to TMB and MSI using a comprehensive cancer panel assay (CCPA) with >500 genes in advanced cancer patients. CCPA results from 588 archived tissue samples were analyzed for TMB and MSI. In seven samples, whole exome sequencing confirmed TMB with Pearson’s correlation coefficient of 0.972 and all MSI-high cases were validated by pentaplex PCR. Association of TMB and MSI with their corresponding PD-L1 IHC was analyzed. The median TMB value of 588 cases was 8.25 mutations (mut)/Mb (range 0–426.8) with different distributions among the tumor types, with high proportions of high-TMB (>10mut/Mb) in tumors from melanoma, colorectal, gastric, and biliary tract. The TMB values significantly correlated with PD-L1 expression, and this correlation was prominent in gastric and biliary tract cancers. Moreover, the MSI score, the proportion of unstable MSI sites to total assessed MSI sites, showed a significant correlation with the TMB values and PD-L1 scores. This study demonstrates that PD-L1 expression is significantly associated with TMB and MSI score and this correlation depends on the location of the primary tumor.
Highlights
Identifying targetable alterations and biomarkers for predicting immunotherapeutic response with limited specimens is crucial [1]
We compared the average depths of sequencing coverage obtained with the bead pooling method (Figure S1A) and manual pooling method (Figure S1B) to assess the sequencing depths and found that the manual pooling method was superior to the bead pooling method
When we increased the amount of DNA input from 80 ng to 120 ng, the average depth coverage increased to 317.1× (Figure S1C)
Summary
Identifying targetable alterations and biomarkers for predicting immunotherapeutic response with limited specimens is crucial [1]. Sex assays to accurately measure microsatellite instability (MSI) and tumor mutation burden (TMB) for predicting responses to immunotherapy. The initial biomarker used to predict the therapeutic response to ICI was the expression of PD-L1. The expression of PD-L1 on tumor cells or tumor-infiltrating immune cells by immunohistochemistry (IHC) has become the most widely used biomarker for selecting patients for ICI therapy [9]. TMB, defined as the total number of mutations per megabase (mut/Mb) in the coding area of a tumor genome, has emerged as a predictive biomarker for response to ICI [7,10,11,12]. Mutated tumors are more likely to produce abundant tumor-specific mutant epitopes functioning as neoantigens and are targeted by the immune system [15,20]
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