Chromosomal Instability May Not Be a Predictor for Immune Checkpoint Inhibitors from a Comprehensive Bioinformatics Analysis.

Chiao-En Wu,Da-Wei Yeh,Yu-Chao Wang,Chun-Nan Yeh,Ming-Huang Chen,John Wen-Cheng Chang,Yi-Ru Pan,Wen-Kuan Huang,Jen-Shi Chen

doi:10.3390/life10110276

Abstract

Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although their predictive tools have not yet completely developed. Here, we aimed to exam the role of 70-gene chromosomal instability signature (CIN70) in cancers, and its association with previous predictors, tumor mutation burden (TMB), and microsatellite instability (MSI), for patients undergoing ICIs, as well as the possible predictive value for ICIs. We examined the association of CIN70 with TMB and MSI, as well as the impact of these biomarkers on the survival of 33 cancer cohorts from The Cancer Genome Atlas (TCGA) databank. The predictive value of the ICIs of CIN70 in previously published reports was also validated. Using the TCGA dataset, CIN70 scores were frequently (either positively or negatively) associated with TMB, but were only significantly associated with MSI status in three types of cancer. In addition, our current study showed that all TMB, MSI, and CIN70 had their own prognostic values for survival in patients with various cancers, and that they could be cancer type-specific. In two validation cohorts (melanoma by Hugo et al. and urothelial cancer by Snyder et al.), no significant difference of CIN70 scores was found between responders and non-responders (p-value = 0.226 and 0.108, respectively). In addition, no overall survival difference was noted between patients with a high CIN70 and those with a low CIN70 (p-value = 0.106 and 0.222, respectively). In conclusion, the current study, through a comprehensive bioinformatics analysis, demonstrated a correlation between CIN70 and TMB, but CIN70 is not the predictor for cancer patients undergoing ICIs. Future prospective studies are warranted to validate these findings.

Highlights

Immune checkpoint inhibitors (ICIs) targeting immune checkpoints, such as the interaction of programmed cell death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1), have been widely used in various solid cancers and have achieved impressive success in cancer treatment, leading to a new eraLife 2020, 10, 276; doi:10.3390/life10110276 www.mdpi.com/journal/lifeLife 2020, 10, 276 of anticancer therapy
To assess the distribution of CIN70 and tumor mutation burden (TMB) across various cancers, we firstly downloaded the gene expression data and somatic mutation data from The Cancer Genome Atlas (TCGA) database, in which data were collected across 33 cancer types
In the current study, using the TCGA dataset, CIN70 was found to be associated with TMB but

Summary

Introduction

Immune checkpoint inhibitors (ICIs) targeting immune checkpoints, such as the interaction of programmed cell death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1), have been widely used in various solid cancers and have achieved impressive success in cancer treatment, leading to a new eraLife 2020, 10, 276; doi:10.3390/life10110276 www.mdpi.com/journal/lifeLife 2020, 10, 276 of anticancer therapy. Immune checkpoint inhibitors (ICIs) targeting immune checkpoints, such as the interaction of programmed cell death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1), have been widely used in various solid cancers and have achieved impressive success in cancer treatment, leading to a new era. In 2020, pembrolizumab was approved for the treatment of tumor mutation burden-high (TMB-H) solid tumors, which are defined as ≥10 mutations/megabase (mut/Mb), as assessed using the FoundationOneCDx assay. Both MSI-H and TMB-H are associated with increased neoantigens, which elicit an immune response during ICI treatment.

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