The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC

Hiroaki Kanemura, Hidetoshi Hayashi, Shuta Tomida, Junko Tanizaki, Shinichiro Suzuki, Yusuke Kawanaka, Asuka Tsuya, Yasushi Fukuda, Hiroyasu Kaneda, Keita Kudo, Takayuki Takahama, Ryosuke Imai, Koji Haratani, Yasutaka Chiba, Tomoyuki Otani, Akihiko Ito, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (−0.18 versus −0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC.

Original languageEnglish
Article number100373
JournalJTO Clinical and Research Reports
Volume3
Issue number8
DOIs
Publication statusPublished - Aug 2022

Keywords

  • Immunotherapy
  • Neoantigen
  • Small cell lung cancer
  • Tumor mutation burden
  • Tumor-infiltrating lymphocyte

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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