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

Authors :
Roper N
Velez MJ
Chiappori A
Kim YS
Wei JS
Sindiri S
Takahashi N
Mulford D
Kumar S
Ylaya K
Trindade C
Manukyan I
Brown AL
Trepel JB
Lee JM
Hewitt S
Khan J
Thomas A
Source :
Nature communications [Nat Commun] 2021 Jun 23; Vol. 12 (1), pp. 3880. Date of Electronic Publication: 2021 Jun 23.
Publication Year :
2021

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.

Details

Language :
English
ISSN :
2041-1723
Volume :
12
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
34162872
Full Text :
https://doi.org/10.1038/s41467-021-24164-y