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. 2023 Dec;129(12):2003-2013.
doi: 10.1038/s41416-023-02427-3. Epub 2023 Sep 20.

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

Masayuki Shirasawa  1   2   3 , Tatsuya Yoshida  4   5 , Kouya Shiraishi  2 , Naoko Goto  1 , Shigehiro Yagishita  6 , Tatsuya Imabayashi  7 , Yuji Matsumoto  1   7 , Ken Masuda  1 , Yuki Shinno  1 , Yusuke Okuma  1 , Yasushi Goto  1 , Hidehito Horinouchi  1 , Masaya Yotsukura  8 , Yukihiro Yoshida  8 , Kazuo Nakagawa  8 , Katsuhiko Naoki  3 , Takaaki Tsuchida  7 , Ryuji Hamamoto  9 , Noboru Yamamoto  1   6 , Noriko Motoi  2   10   11 , Takashi Kohno  2 , Shun-Ichi Watanabe  8 , Yuichiro Ohe  1
Affiliations

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

Masayuki Shirasawa et al. Br J Cancer. 2023 Dec.

Erratum in

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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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1. Features and Prognostic role of DLL3 expressions in LS-SCLC cohort.
a Comparison of the median gene expression of MKi67, SYP1, CGA, NCAM, and ASCL1 between high and low DLL3 expression tumors. b Heatmaps: expression of neuroendocrine (NE) marker and non-NE marker expression profile according to DLL3 expression. c Illustration of histology. Examples of each immunohistochemistry (IHC) (DLL3, Ki-67, synaptophysin, chromogranin A, CD56, and ASCL1) of high and low DLL3 expression tumors are shown. Small-cell carcinomas with high DLL3 expression (top row) show a higher Ki-67 labeling index and distinct expression of NE differentiation markers than those with low DLL3 expression (lower row) (All images, ×40 magnification). d Correlation between DLL3 and SCLC markers based on IHC. e Relapse-free survival (RFS) according to DLL3 expression (DLL3High [red line] and DLL3Low [blue line]).
Fig. 2
Fig. 2. Genomic driver landscape and Genomic status in LS-SCLC cohort.
a Presented gene mutations had a frequency of ≥3% in OncoPrint. Reported frequencies include a composite of all alterations for each gene between high and low DLL3 expression tumors. The information of each patient showed pathology (SCLC or combined SCLC), transcriptional expression of DLL3, tumor mutational burden (TMB), neoantigens, and rate of mutation signature. b–d Comparison of median TMB, the rate of mutation signature, and the number of expressed neoantigens (IC50 < 500 nM) between high and low DLL3 expression tumors.
Fig. 3
Fig. 3. Transcriptomic characterization of DLL3 expression in LS-SCLC cohort.
a, b MSigDB Hallmark gene sets associated with SCLC with high DLL3 expression in limited-stage-small-cell lung cancer cohort (adjusted P < 0.05). Ridgeplot (a) shows a normalized enrichment score based on Gene Set Enrichment Analysis (GSEA). The dot plot (b) shows the gene ratio based on GSEA. c CIBERSORTx analysis of specific immune cell populations between high and low DLL3 expression tumors. d 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. e Comparison of median gene expression of T-cell GEP score and chemokine signature (right figure) between high and low DLL3 expression tumors.
Fig. 4
Fig. 4. Association of DLL3 expression with IFN and dendritic function in transcriptome analysis.
a, b Gene Set Enrichment Analysis (GSEA) plots showing the gene enrichment patterns of response to type I interferon (IFN) (a, left), IFN-alpha (A, middle), IFN-beta (a, right), dendritic cell differentiation (b, left), dendritic cell antigen processing and presentation (b, middle), and dendritic cell migration (b, right) between high and low DLL3 expression tumors. Normalized enrichment score (NES), q value, and P values are shown on the plots. c Comparison of median gene expression of E2F and STING (TMEM173) between high and low DLL3 expression tumors. d Heatmaps: expression of Rb1, E2F, and STING (TMEM173) according to DLL3 expression are shown. e GSEA plots showing the gene enrichment patterns of E2F targets (c, left), Cell cycle (c, right) between high and low DLL3 expression tumors.
Fig. 5
Fig. 5. PFS of immunochemotherapy and GSEA analysis according to DLL3 expression in ES-SCLC cohort.
a Progression-free survival (PFS) of patients treated with platinum and etoposide (PE) plus anti-PD-L1 antibody according to DLL3 expression (patients with DLL3High [red line], patients with DLL3Low [blue line]). b, c MSigDB Hallmark gene sets associated with SCLC with DLL3High expression in extensive-stage-small-cell lung cancer cohort (adjusted P < 0.05). Ridgeplot (b) shows the normalized enrichment score based on Gene Set Enrichment Analysis (GSEA). The dot plot (c) shows the gene ratio based on GSEA.
See this image and copyright information in PMC

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