Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation

  • Sci Adv. 2023 May 19;9(20):eade0718. doi: 10.1126/sciadv.ade0718.
Yujiro Naito  1  2  3 ,  Shohei Koyama  1  2  4 ,  Kentaro Masuhiro  1  3 ,  Takashi Hirai  3  5 ,  Takeshi Uenami  6 ,  Takako Inoue  7 ,  Akio Osa  1 ,  Hirotomo Machiyama  1 ,  Go Watanabe  4 ,  Nicolas Sax  8 ,  Jordan Villa  8 ,  Yumi Kinugasa-Katayama  9 ,  Satoshi Nojima  10 ,  Moto Yaga  1  3 ,  Yuki Hosono  1  11  12 ,  Daisuke Okuzaki  13  14  15 ,  Shingo Satoh  1  3 ,  Takeshi Tsuda  5 ,  Yoshimitsu Nakanishi  1  3 ,  Yasuhiko Suga  1 ,  Takayoshi Morita  1  3 ,  Kiyoharu Fukushima  1  16 ,  Masayuki Nishide  1  3 ,  Takayuki Shiroyama  1 ,  Kotaro Miyake  1 ,  Kota Iwahori  1 ,  Haruhiko Hirata  1 ,  Izumi Nagatomo  1 ,  Yukihiro Yano  6 ,  Motohiro Tamiya  7 ,  Toru Kumagai  7 ,  Norihiko Takemoto  5 ,  Hidenori Inohara  5 ,  Sho Yamasaki  11  12 ,  Kazuo Yamashita  8 ,  Taiki Aoshi  9 ,  Esra A Akbay  17 ,  Naoki Hosen  14  18  19 ,  Yasushi Shintani  20 ,  Hyota Takamatsu  1  3 ,  Masahide Mori  6 ,  Yoshito Takeda  1 ,  Atsushi Kumanogoh  1  2  3  14  15  21  22
Affiliations
  • 1. Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
  • 2. Department of Immunology and Molecular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
  • 3. Department of Immunopathology, World Premier International Research Center (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan.
  • 4. Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa,Chiba, and Tokyo, Japan.
  • 5. Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
  • 6. Department of Thoracic Oncology, National Hospital Organization, Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan.
  • 7. Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
  • 8. KOTAI Biotechnologies Inc., Suita, Osaka, Japan.
  • 9. Department of Cellular Immunology, Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, Osaka, Japan.
  • 10. Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
  • 11. Laboratory of Molecular Immunology, WPI, IFReC, Osaka University, Suita, Osaka, Japan.
  • 12. Department of Molecular Immunology, RIMD, Osaka University, Suita, Osaka, Japan.
  • 13. Single Cell Genomics, Human Immunology, WPI, IFReC, Osaka University, Suita, Osaka, Japan.
  • 14. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan.
  • 15. Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Suita, Osaka, Japan.
  • 16. Laboratory of Host Defense, WPI, IFReC, Osaka University, Suita, Osaka, Japan.
  • 17. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 18. Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
  • 19. Laboratory of Cellular Immunotherapy, WPI, IFReC, Osaka University, Suita, Osaka, Japan.
  • 20. Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
  • 21. Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Suita, Osaka, Japan.
  • 22. Center for Advanced Modalities and DDS (CAMaD), Osaka University, Suita, Osaka, Japan.
Abstract

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in Cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive Non-Small Cell Lung Cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by Recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with Cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

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