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.

• Nabet, B. Y.
• Hamidi, H.
• Lee, M. C.
• Banchereau, R.
• Morris, S.
• Adler, L.
• Gayevskiy, V.
• Elhossiny, A. M.
• Srivastava, M. K.
• Patil, N. S.
• Smith, K. A.
• Jesudason, R.
• Chan, C.
• Chang, P. S.
• Fernandez, M.
• Rost, S.
• McGinnis, L. M.
• Koeppen, H.
• Gay, C. M.
• Minna, J. D.
• Heymach, J. V.
• Chan, J. M.
• Rudin, C. M.
• Byers, L. A.
• Liu, S. V.
• Reck, M.
• Shames, D. S.