Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer
© 2023. The Author(s), under exclusive licence to Springer Nature Limited..
BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear.
METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy.
RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01).
CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:129 |
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| Enthalten in: |
British journal of cancer - 129(2023), 12 vom: 01. Dez., Seite 2003-2013 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shirasawa, Masayuki [VerfasserIn] |
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Date Completed 16.12.2023 Date Revised 05.03.2024 published: Print-Electronic ErratumIn: Br J Cancer. 2023 Nov 3;:. - PMID 37923915 Citation Status MEDLINE |
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| doi: |
10.1038/s41416-023-02427-3 |
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NLM362277672 |
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| 100 | 1 | |a Shirasawa, Masayuki |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer |
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| 500 | |a Date Revised 05.03.2024 | ||
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| 500 | |a ErratumIn: Br J Cancer. 2023 Nov 3;:. - PMID 37923915 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s), under exclusive licence to Springer Nature Limited. | ||
| 520 | |a BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear | ||
| 520 | |a METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy | ||
| 520 | |a RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01) | ||
| 520 | |a CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Yagishita, Shigehiro |e verfasserin |4 aut | |
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