Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer

Nitin Roper,Kris Ylaya,Jung-Min Lee,Sivasish Sindiri,Stephen Hewitt,Jun S Wei,Jane B Trepel,Moises J Velez,Anish Thomas,Javed Khan,Irena Manukyan,Nobuyuki Takahashi,Yoo Sun Kim,Suresh Kumar,Alberto Chiappori,Anna-Leigh Brown,Christopher Trindade,Deborah Mulford

doi:10.1038/s41467-021-24164-y

Abstract

Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC), yet the mechanisms driving benefit are poorly understood. To identify predictors of clinical benefit to ICB, we performed immunogenomic profiling of tumor samples from patients with relapsed SCLC. Tumors of patients who derive clinical benefit from ICB exhibit cytotoxic T-cell infiltration, high expression of antigen processing and presentation machinery (APM) genes, and low neuroendocrine (NE) differentiation. However, elevated Notch signaling, which positively correlates with low NE differentiation, most significantly predicts clinical benefit to ICB. Activation of Notch signaling in a NE human SCLC cell line induces a low NE phenotype, marked by increased expression of APM genes, demonstrating a mechanistic link between Notch activation, low NE differentiation and increased intrinsic tumor immunity. Our findings suggest Notch signaling as a determinant of response to ICB in SCLC.

Highlights

Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC), yet the mechanisms driving benefit are poorly understood
Using prospective and retrospective anti-progressive disease (PD)-1/programmed death ligand 1 (PD-L1) antibody-treated SCLC cohorts, we find an association between high expression of Notch pathway genes and clinical benefit (CB) to ICB
Our discovery cohort was derived from a prospective clinical trial of 20 previously treated patients with SCLC who received durvalumab, an anti-PD-L1 antibody administered every 4 weeks and olaparib, a poly (ADPribose) polymerase (PARP) inhibitor administered twice daily[15] (Fig. 1a)

Summary

Introduction

Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC), yet the mechanisms driving benefit are poorly understood. To identify predictors of clinical benefit to ICB, we performed immunogenomic profiling of tumor samples from patients with relapsed SCLC. Tumors of patients who derive clinical benefit from ICB exhibit cytotoxic T-cell infiltration, high expression of antigen processing and presentation machinery (APM) genes, and low neuroendocrine (NE) differentiation. For first-line treatment of SCLC, the addition of atezolizumab, an anti-programmed death ligand 1 (PD-L1) antibody, to carboplatin and etoposide in the phase 3 IMpower[133] trial[3] significantly improved median survival from 10.3 to 12.3 months; only 12.6% of patients remained progression-free at 1 year. Improved ICB response rates were suggested in relapsed SCLC with high TMB in one retrospective study[13], but in the IMpower[133] trial[3], treatment benefit was observed regardless of pre-specified TMB thresholds. SCLC is not included in The Cancer Genome Atlas (TCGA) that contains over 11,000 tumors from more than 30 different tumor types

Methods

Results

Conclusion