Immune heterogeneity in small-cell lung cancer and vulnerability to immune checkpoint blockade

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.