Faculty, Staff and Student Publications

Publication Date

3-11-2024

Journal

Cancer Cell

DOI

10.1016/j.ccell.2024.01.010

PMID

38366589

Abstract

Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses.

Keywords

Humans, Lung Neoplasms, Immune Checkpoint Inhibitors, Small Cell Lung Carcinoma, Carboplatin, Etoposide, Immunotherapy, IMpower133, atezolizumab, immune checkpoint blockade, immunotherapy, molecular subtyping, small cell lung cancer, transcriptomics, tumor-associated macrophages

Published Open-Access

yes

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