Identification of inflamed-phenotype of small cell lung cancer leading to the efficacy of anti-PD-L1 antibody and chemotherapy

Masayuki Shirasawa; Tatsuya Yoshida; Kouya Shiraishi; Ayako Takigami; Daisuke Takayanagi; Tatsuya Imabayashi; Yuji Matsumoto; Ken Masuda; Yuki Shinno; Yusuke Okuma; Yasushi Goto; Hidehito Horinouchi; Masaya Yotsukura; Yukihiro Yoshida; Kazuo Nakagawa; Takaaki Tsuchida; Ryuji Hamamoto; Noboru Yamamoto; Noriko Motoi; Takashi Kohno; Shun-Ichi Watanabe; Yuichiro Ohe

doi:10.1016/j.lungcan.2023.107183

Identification of inflamed-phenotype of small cell lung cancer leading to the efficacy of anti-PD-L1 antibody and chemotherapy

Lung Cancer. 2023 May:179:107183. doi: 10.1016/j.lungcan.2023.107183. Epub 2023 Mar 25.

Authors

Masayuki Shirasawa¹, Tatsuya Yoshida², Kouya Shiraishi³, Ayako Takigami⁴, Daisuke Takayanagi³, Tatsuya Imabayashi⁵, Yuji Matsumoto⁶, Ken Masuda⁷, Yuki Shinno⁷, Yusuke Okuma⁷, Yasushi Goto⁷, Hidehito Horinouchi⁷, Masaya Yotsukura⁸, Yukihiro Yoshida⁸, Kazuo Nakagawa⁸, Takaaki Tsuchida⁵, Ryuji Hamamoto⁹, Noboru Yamamoto¹⁰, Noriko Motoi¹¹, Takashi Kohno³, Shun-Ichi Watanabe⁸, Yuichiro Ohe⁷

Affiliations

¹ Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0375, Japan.
² Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. Electronic address: tatyoshi@ncc.go.jp.
³ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁴ Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi,329-0498,Japan.
⁵ Department of Endoscopy, Respiratory Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan, 104-0045, Japan.
⁶ Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Department of Endoscopy, Respiratory Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan, 104-0045, Japan.
⁷ Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
⁸ Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
⁹ Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, 104-0045, Japan.
¹⁰ Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
¹¹ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Department of Pathology, Saitama Cancer Center, Saitama, 362-0806, Japan.

PMID: 37037178
DOI: 10.1016/j.lungcan.2023.107183

Abstract

Background: Platinum etoposide plus anti-programmed cell death ligand-1 (PD-L1) antibody therapy is the standard of care for extensive-stage small cell lung cancer (ES-SCLC). However, patient characteristics associated with the efficacy of the combination therapy in SCLC are unclear.

Methods: We retrospectively reviewed post-surgical limited-stage (LS)-SCLC and ES-SCLC patients treated with atezolizumab plus carboplatin and etoposide (ACE). The association between SCLC subtypes based on transcriptomic data and pathological findings, including CD8-positive tumor-infiltrating lymphocyte (TIL) status, was investigated in the LS-SCLC cohort. The association between the efficacy of ACE therapy, pathological subtypes, and TIL status was evaluated in the ES-SCLC cohort.

Results: The LS-SCLC cohort (N = 48) was classified into four SCLC subtypes (ASCL1 + NEUROD1 [SCLC-A + N, N = 17], POU2F3 [SCLC-P, N = 15], YAP1 [SCLC-Y, N = 10], and inflamed [SCLC-I, N = 6]) based on transcriptomic data. SCLC-I showed enriched immune-related pathways, the highest immune score (CD8A expression and T-cell-inflamed gene expression profiles), and epithelial-mesenchymal transition (EMT), in transcriptional subtypes. Immunohistochemical staining (IHC) showed that SCLC-I had the highest density of CD8-positive TILs in transcriptional subtypes. In the ES-SCLC cohort, the efficacy of ACE therapy did not differ according to pathological subtypes. The progression-free survival (PFS) of TIL_High patients was significantly longer than that of TIL_Low patients (PFS: 7.3 months vs. 4.0 months, p < 0.001).

Conclusion: Tumors with a high density of TILs, which represent the most immunogenic SCLC subtype (SCLC-I), based on transcriptomic data could benefit from ACE therapy.

Keywords: Platinum etoposide (ETP) plus programmed cell death ligand-1 (PD-L1) antibody therapy; SCLC subtypes; Small cell lung cancer (SCLC); Tumor-infiltrating lymphocyte (TIL).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Etoposide / therapeutic use
Humans
Lung Neoplasms* / drug therapy
Phenotype
Retrospective Studies
Small Cell Lung Carcinoma* / drug therapy

Substances

Etoposide