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

Barzin Y. Nabet; Habib Hamidi; Myung Chang Lee; Romain Banchereau; Stefanie Morris; Leah Adler; Velimir Gayevskiy; Ahmed M. Elhossiny; Minu K. Srivastava; Namrata S. Patil; Kiandra A. Smith; Rajiv Jesudason; Caleb Chan; Patrick S. Chang; Matthew Fernandez; Sandra Rost; Lisa M. McGinnis; Hartmut Koeppen; Carl M. Gay; John D. Minna; John V. Heymach; Joseph M. Chan; Charles M. Rudin; Lauren A. Byers; Stephen V. Liu; Martin Reck; David S. Shames

doi:10.1016/j.ccell.2024.01.010

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

Barzin Y. Nabet, Habib Hamidi, Myung Chang Lee, Romain Banchereau, Stefanie Morris, Leah Adler, Velimir Gayevskiy, Ahmed M. Elhossiny, Minu K. Srivastava, Namrata S. Patil, Kiandra A. Smith, Rajiv Jesudason, Caleb Chan, Patrick S. Chang, Matthew Fernandez, Sandra Rost, Lisa M. McGinnis, Hartmut Koeppen, Carl M. Gay, John D. MinnaJohn V. Heymach, Joseph M. Chan, Charles M. Rudin, Lauren A. Byers, Stephen V. Liu, Martin Reck, David S. Shames

Thoracic Head & Neck Medical Oncology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	429-443.e4
Journal	Cancer cell
Volume	42
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2024.01.010
State	Published - Mar 11 2024

Keywords

atezolizumab
immune checkpoint blockade
immunotherapy
IMpower133
molecular subtyping
small cell lung cancer
transcriptomics
tumor-associated macrophages

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2024.01.010

Cite this

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., ... Shames, D. S. (2024). Immune heterogeneity in small-cell lung cancer and vulnerability to immune checkpoint blockade. Cancer cell, 42(3), 429-443.e4. https://doi.org/10.1016/j.ccell.2024.01.010

Nabet, BY, Hamidi, H, Lee, MC, Banchereau, R, Morris, S, Adler, L, Gayevskiy, V, Elhossiny, AM, Srivastava, MK, Patil, NS, Smith, KA, Jesudason, R, Chan, C, Chang, PS, Fernandez, M, Rost, S, McGinnis, LM, Koeppen, H, Gay, CM, Minna, JD, Heymach, JV, Chan, JM, Rudin, CM, Byers, LA, Liu, SV, Reck, M & Shames, DS 2024, 'Immune heterogeneity in small-cell lung cancer and vulnerability to immune checkpoint blockade', Cancer cell, vol. 42, no. 3, pp. 429-443.e4. https://doi.org/10.1016/j.ccell.2024.01.010

@article{762bc349ed8d463cafd2fb7e07bcce52,

title = "Immune heterogeneity in small-cell lung cancer and vulnerability to immune checkpoint blockade",

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 = "atezolizumab, immune checkpoint blockade, immunotherapy, IMpower133, molecular subtyping, small cell lung cancer, transcriptomics, tumor-associated macrophages",

author = "Nabet, {Barzin Y.} and Habib Hamidi and Lee, {Myung Chang} and Romain Banchereau and Stefanie Morris and Leah Adler and Velimir Gayevskiy and Elhossiny, {Ahmed M.} and Srivastava, {Minu K.} and Patil, {Namrata S.} and Smith, {Kiandra A.} and Rajiv Jesudason and Caleb Chan and Chang, {Patrick S.} and Matthew Fernandez and Sandra Rost and McGinnis, {Lisa M.} and Hartmut Koeppen and Gay, {Carl M.} and Minna, {John D.} and Heymach, {John V.} and Chan, {Joseph M.} and Rudin, {Charles M.} and Byers, {Lauren A.} and Liu, {Stephen V.} and Martin Reck and Shames, {David S.}",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = mar,

day = "11",

doi = "10.1016/j.ccell.2024.01.010",

language = "English (US)",

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T1 - Immune heterogeneity in small-cell lung cancer and vulnerability to immune checkpoint blockade

AU - Nabet, Barzin Y.

AU - Hamidi, Habib

AU - Lee, Myung Chang

AU - Banchereau, Romain

AU - Morris, Stefanie

AU - Adler, Leah

AU - Gayevskiy, Velimir

AU - Elhossiny, Ahmed M.

AU - Srivastava, Minu K.

AU - Patil, Namrata S.

AU - Smith, Kiandra A.

AU - Jesudason, Rajiv

AU - Chan, Caleb

AU - Chang, Patrick S.

AU - Fernandez, Matthew

AU - Rost, Sandra

AU - McGinnis, Lisa M.

AU - Koeppen, Hartmut

AU - Gay, Carl M.

AU - Minna, John D.

AU - Heymach, John V.

AU - Chan, Joseph M.

AU - Rudin, Charles M.

AU - Byers, Lauren A.

AU - Liu, Stephen V.

AU - Reck, Martin

AU - Shames, David S.

PY - 2024/3/11

Y1 - 2024/3/11

N2 - 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.

AB - 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.

KW - atezolizumab

KW - immune checkpoint blockade

KW - immunotherapy

KW - IMpower133

KW - molecular subtyping

KW - small cell lung cancer

KW - transcriptomics

KW - tumor-associated macrophages

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U2 - 10.1016/j.ccell.2024.01.010

DO - 10.1016/j.ccell.2024.01.010

M3 - Article

C2 - 38366589

AN - SCOPUS:85186639024

SN - 1535-6108

VL - 42

SP - 429-443.e4

JO - Cancer cell

JF - Cancer cell

IS - 3

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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