Evaluation of immune checkpoints in small cell lung cancer: implications for immunotherapy

Abstract

Abstract Introduction The FDA recently approved Atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor, for first-line combinatory treatment in patients with extensive-stage small cell lung cancer. Across several cancer types, immunotherapy has been shown to provide durable benefit in patients with metastatic disease. However, Atezolizumab only improves overall survival by 2 months. This could be due to the fact that <20% of patients express >1% tumor PD-L1 positivity. We assert that a better understanding of this immune contexture – defined as abundance and type of checkpoint molecules in SCLC – may provide important criteria for patient stratification. Objectives In these studies, we will test the hypothesis that immune checkpoints in addition to the PD-1/PD-L1 axis play a role in immune evasion in SCLC. Methods To evaluate expression of immune checkpoint molecules, we acquired bulk RNA-Seq data of SCLC cell lines and primary tumor specimens. Further, we generated tissue-microarrays containing >20 unique cell lines and >200 unique patient specimens with fully annotated clinical data to confirm expression of these molecules by immunohistochemistry. Results Preliminary RNA-Seq analyses show low PD-L1 expression in SCLC cell lines and primary tumors. Further, ubiquitously high expression of certain checkpoint molecules (B7-H3) is seen. Future analysis will confirm abundance and type of checkpoint molecules as well as capture interpatient heterogeneity. Conclusions Understanding the checkpoint molecules present in SCLC could further understanding of SCLC immune suppression, ultimately leading to optimal single-agent immunotherapy deployment and rational, effective combination therapy for patients with SCLC.