Molecular-Based Predictive Biomarkers of Response to Immune Checkpoint Blockade - Expert Commentary

Immune checkpoint blockade (ICB) is associated with durable responses in a select group of patients with advanced cancer achieving. However, attempts to define biomarkers to identify this subgroup of exceptional responders have been elusive. Pan-tumor predictive biomarkers to PD-L1 blockade are lacking.

A recent study by Banchereau et al. published in Nature Communications investigated the molecular determinants of response to PD-L1 blockade across different cancer types. The investigators performed molecular analysis of archived tissue from three atezolizumab monotherapy studies, including patients with advanced urothelial cancer (UC, n=208), non-small cell lung cancer (NSCLC, n= 81), and renal cell carcinoma (RCC, n= 77). PD-L1 expression by immunohistochemistry and tumor mutational burden (TMB) (categorized based on the median, 16.3 mutations/megabase) had poor predictive capacity.

The investigators performed bulk RNA sequencing of pretreatment tumor samples. A machine learning-based method was applied to identify a transcriptional signature predictive to atezolizumab and complement PD-L1 expression and TMB. A 58-gene signature was identified in this cohort with a receiver operating characteristic (ROC) curve of AUC=0.99. Applying this signature in another independent cohort of advanced UC, NSCLC, and RCC tumors treated with atezolizumab in a phase I basket clinical trial showed low performance in predicting response (AUC<0.65).

The investigators identified the genes differentially expressed between anti-PD-L1 responders and nonresponses. Upregulation of CDKN2A was enriched in the responding subgroup. On the other hand, there was a trend toward poor response rates in tumors with CDKN2A loss. These observations support the rationale for combining CDK4/6 inhibitors with ICB. However, the challenge of establishing predictive signatures reflects the significant heterogeneity in the mechanisms of response to ICB and requires an individualized approach.    

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Banchereau R, Leng N, Zill O, Sokol E, Liu G, Pavlick D, et al. Molecular determinants of response to PD-L1 blockade across tumor types. Nat Commun. 2021;12(1):1–11. PMID: 34172722

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