Spatial dynamics of CD39+CD8+ exhausted T cell reveal tertiary lymphoid structures-mediated response to PD-1 blockade in esophageal cancer
Despite the success of immune checkpoint blockade (ICB) therapy for esophageal squamous cell cancer, the key immune cell populations that affect ICB efficacy remain unclear. Here, imaging mass cytometry of tumor tissues from ICB-treated patients identifies a distinct cell population of CD39<sup>+</sup>PD-1<sup>+</sup>CD8<sup>+</sup> T cells, specifically the TCF1<sup>+</sup> subset, precursor exhausted T (CD39<sup>+</sup> Tpex) cells, which positively correlate with ICB benefit. CD39<sup>+</sup> Tpex cells are predominantly in the stroma, while differentiated CD39<sup>+</sup> exhausted T cells are abundantly and proximally within the parenchyma. Notably, CD39<sup>+</sup> Tpex cells are concentrated within and around tertiary lymphoid structure (TLS). Accordingly, tumors harboring TLSs have more of these cells in tumor areas than tumors lacking TLSs, suggesting Tpex cell recruitment from TLSs to tumors. In addition, circulating CD39<sup>+</sup> Tpex cells are also increased in responders following ICB therapy. Our findings show that this unique subpopulation of CD39<sup>+</sup>PD-1<sup>+</sup>CD8<sup>+</sup> T cells is crucial for ICB benefit, and suggest a key role in TLS-mediated immune responses against tumors.
Authors
- Takeshi Iwasaki (ORCID: https://orcid.org/0000-0001-5277-2932)
- Kenro Tanoue (ORCID: https://orcid.org/0009-0005-0583-4412)
- Kenji Tsuchihashi (ORCID: https://orcid.org/0000-0002-9014-6382)
- Peng Lu (ORCID: https://orcid.org/0000-0003-3259-474X)
- Yoshinao Oda (ORCID: https://orcid.org/0000-0001-9636-1182)
- Hiroshi Ariyama (ORCID: https://orcid.org/0000-0002-8374-5045)
- Yoshihiro Shibata (ORCID: https://orcid.org/0000-0001-9009-4343)
- Hidetaka Yamamoto (ORCID: https://orcid.org/0000-0001-9148-6445)
- Taito Esaki (ORCID: https://orcid.org/0000-0002-9169-8453)
- Mamoru Ito (ORCID: https://orcid.org/0000-0002-5373-8223)
- Hirofumi Ohmura (ORCID: https://orcid.org/0000-0003-4650-9120)
- Hitoshi Kusaba (ORCID: https://orcid.org/0000-0002-2949-5970)
- Eishi Baba (ORCID: https://orcid.org/0000-0001-9428-6772)
- Daisuke Kiyozawa (ORCID: https://orcid.org/0000-0002-3761-8491)
- Risa Tanaka
- Taichi Isobe (ORCID: https://orcid.org/0000-0001-5686-1940)
- Koki Uehara
- Koichi Akashi (ORCID: https://orcid.org/0000-0001-7763-5723)
- Toshihiro Yamaguchi (ORCID: https://orcid.org/0000-0002-5458-5345)
- Hozumi Shimokawa
- Kenji Mitsugi
- Shingo Tamura
- Yudai Shinohara
Institutions
- Kyushu University (JP)
- Okayama University (JP)
- Washington University in St. Louis (US)
- National Kyushu Medical Center (JP)
- St Mary's Hospital (JP)
- Sasebo City General Hospital (JP)
- National Hospital Organization Kyushu Cancer Center (JP)
- Hamanomachi Hospital (JP)
- Kyushu Hospital (JP)
- Kitakyushu Municipal Medical Center (JP)
- Uji Hospital (JP)
- Japan Community Healthcare Organization (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-19
- DOI
- https://doi.org/10.1038/s41467-024-53262-w
- Citations
- 24
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 6.78
Funders
- Forskningsrådet om Hälsa, Arbetsliv och Välfärd
- Japan Society for the Promotion of Science