Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation PMID: 37205755

ADC Targets in Oncology

2026-04-10

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.