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Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer

British Journal of Cancer volume 129, pages 2003–2013 (2023)Cite this article

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A Correction to this article was published on 03 November 2023

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Abstract

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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Fig. 1: Features and Prognostic role of DLL3 expressions in LS-SCLC cohort.
Fig. 2: Genomic driver landscape and Genomic status in LS-SCLC cohort.
Fig. 3: Transcriptomic characterization of DLL3 expression in LS-SCLC cohort.
Fig. 4: Association of DLL3 expression with IFN and dendritic function in transcriptome analysis.
Fig. 5: PFS of immunochemotherapy and GSEA analysis according to DLL3 expression in ES-SCLC cohort.

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Data availability

The datasets generated during and/or analyzed during this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank all patients who contributed to this study. We also thank all the investigators from the oncologic department of the National Cancer Center Hospital for their contributions.

Funding

This study was supported in part by the Grant for Lung Cancer Research from MEXT kakenhi Grant-in-Aid for Scientific Research (C) (Grant number 23K07615), the Japan Lung Cancer Society (TY), AMED (22hk0102080h0002), MEXT kakenhi Grant-in-Aid for Scientific Research (C) (Grant number 21K06900) (NM), JST AIP-PRISM (Grant Number JPMJCR18Y4), and MHLW ICT infrastructure establishment and implementation of artificial intelligence for the clinical and medical research program (Grant Number JP21AC5001) (RH).

Author information

Authors and Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo‐ku, Tokyo, 104-0045, Japan

    Masayuki Shirasawa, Tatsuya Yoshida, Naoko Goto, Yuji Matsumoto, Ken Masuda, Yuki Shinno, Yusuke Okuma, Yasushi Goto, Hidehito Horinouchi, Noboru Yamamoto & Yuichiro Ohe

  2. Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Masayuki Shirasawa, Kouya Shiraishi, Noriko Motoi & Takashi Kohno

  3. Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0375, Japan

    Masayuki Shirasawa & Katsuhiko Naoki

  4. Division of Molecular Pharmacology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Tatsuya Yoshida, Shigehiro Yagishita & Noboru Yamamoto

  5. Department of Endoscopy, Respiratory Endoscopy Division, National Cancer Center Hospital, Tokyo, 104-0045, Japan

    Tatsuya Imabayashi, Yuji Matsumoto & Takaaki Tsuchida

  6. Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Masaya Yotsukura, Yukihiro Yoshida, Kazuo Nakagawa & Shun-ichi Watanabe

  7. Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, 104-0045, Japan

    Ryuji Hamamoto

  8. Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Noriko Motoi

  9. Department of Pathology, Saitama Cancer Center, Saitama, 362-0806, Japan

    Noriko Motoi

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  1. Masayuki Shirasawa
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Contributions

MS, TY and NM participated in the study conception and design, data collection, data analysis, reviewed the paper and approved the final draft for submission. TY and NM participated in the study conception and design, funding acquisition, data collection, data analysis, reviewed the paper and approved the final draft for submission. RH participated in data collection, reviewed the paper and approved the final draft for submission. KS, NG and SY participated in the study data collection, funding acquisition, data analysis, reviewed the paper. YM, YS, YO, YG, HH, MY, YY, K Nakagawa, K Naoki, TT, TK, NY, SW and YO participated in data collection, reviewed the paper and approved the final draft for submission.

Corresponding author

Correspondence to Tatsuya Yoshida.

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Dr. TY reports grants from Takeda, Daiichi-Sankyo, AbbVie, and Bristol-Myers Squibb; grants and personal fees from Ono, Novartis, Merck Sharp & Dohme, and Amgen; and personal fees from AstraZeneca. KK reports personal fees from Chugai, ArcherDX, Eli Lilly, Roche, and Taiho outside the submitted work. Dr. YM reports grants from Grant-in-Aid for Scientific Research on Innovative Areas, Hitachi, Ltd., the National Cancer Center Research and Development Fund, and Olympus, and personal fees from AstraZeneca. Drs. MS, KS, NG, SY, TI, KM, MY, YY, K Nakagawa, and S-iW declare no competing interests. Dr. YS reports grants from Janssen and Japan Clinical Research Operations. KK reports personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, and Ono outside the submitted work. Dr. YO reports grants from AbbVie, grants from Roche, and personal fees from Bristol-Myers Squibb Grants, Nippon Boehringer Ingelheim, and AstraZeneca. KK reports personal fees from Chugai, Eli Lilly, Ono Pharma Co. Ltd., Taiho, and Pfizer Taiho Pharma Co. Ltd., outside the submitted work. Dr. YO reports grants from AbbVie, Bristol-Myers Squibb Grants, Kyorin, and Preferred Network; and grants and personal fees from AZK, Daiichi-Sankyo, Eli Lilly, Ono, Novartis, and Pfizer; and personal fees from AstraZeneca. KK reports personal fees from Boehringer Ingelheim, Chugai, Guardant Health Inc., Illumina, Merck Sharp & Dohme, Taiho, and Thermo Fisher outside the submitted work. Dr. HH reports grants and personal fees from Chugai, Ono, and Roche; grants from AbbVie, Bristol-Myers Squibb, Daiichi-Sankyo, Genomic Health, Janssen, and Merck Biopharma, and personal fees from AstraZeneca. KK reports personal fees from Merck Sharp & Dohme, Novartis, Eli Lilly, and Kyowa-Kirin, outside the submitted work. Dr. K Naoki reports personal fees from AstraZeneca, Chugai Pharmaceutical, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim outside the submitted work. Dr. TT reports grants from Japan Agency for Medical Research and Development, and Foundation for Promotion Cancer Research Grant for Medical Research, and personal fees from Nippon Medical School Foundation, outside the submitted work. Dr. RH reports grants from JST AIP-PRISM (Grant Number JPMJCR18Y4), from null, outside the submitted work. Dr. Yamamoto reports grants from Chugai, Taiho, Eisai, Lilly, Quintiles, Astellas, BMS, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, ONO PHARMACEUTICAL CO., LTD, and Takeda; and personal fees from ONO PHARMACEUTICAL CO., LTD, Chugai, Eisai, Boehringer Ingelheim, and Cmic; and grants from Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience Inc., Otsuka, Carna Biosciences, Genmab, TORAY, KAKEN, Shionogi, AstraZeneca, and Cmic; and personal fees from Eisai, Daiichi-Sankyo, MERCK, and Healios, outside the submitted work. Dr. RH reports grants from NEC and Ono, and personal fees from AstraZeneca, Chugai, MSD, Novartis, Roche, Daiichi-Sankyo, Takeda, Eli Lilly, and Janssen, outside the submitted work. Dr. TK reports grants from AMED, outside the submitted work. Dr. YO reports grants from Taiho, Eli Lilly, Kyorin, Daiichi-Sankyo, Dainippon-Sumitomo, Janssen, Kissei, LOXO, Novartis, and Takeda, and personal fees from AstraZeneca. KK reports personal fees from Amgen, AnHeeart Therapeutics Inc., Bayer, Bristol-Myers Squibb, Celltrion, Chugai, Kyowa-Hakko Kirin, Merck Sharp & Dohme, Nippon Kayaku, Ono Pharmaceutical Co., Ltd., Pfizer, Taiho, and Eli Lilly, outside the submitted work.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the National Cancer Center Hospital (2005-109, 2019-123). The written informed consent was obtained from each patient through the comprehensive consent form in the facilities. The study was performed in accordance with the Declaration of Helsinki.

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Not applicable.

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The original online version of this article was revised: The original online version of this article was revised: In the caption of fig 3d is typo. The sentence “The top box indicates the DLL3 expression (z score). Heatmaps: expression of 18-gene-γ-related T-cell gene expression profiles (T-cell GEPs) and 13 chemokine markers of high and low DLL3 expression tumors are shown.” should read “The top box indicates the DLL3 expression (z score). Heatmaps: expression of 18-gene-γ-related T-cell gene expression profiles (T-cell GEPs) and 12 chemokine markers of high and low DLL3 expression tumors are shown”.

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Shirasawa, M., Yoshida, T., Shiraishi, K. et al. Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer. Br J Cancer 129, 2003–2013 (2023). https://doi.org/10.1038/s41416-023-02427-3

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