Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8<sup>+</sup> T cell responses and promoting tertiary lymphoid structure formation.
Overview
- Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
- Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Digital Transformation in Healthcare and Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
- Division of Multicellular Circuit Dynamics, National Institute for Physiological Sciences, Okazaki, Japan
- Department of Physiological Sciences, Graduate University for Advanced Studies, SOKENDAI, Hayama, Japan
Abstract
Brain metastases (BrMs) in non-small cell lung cancer (NSCLC) respond poorly to anti-PD-1 monotherapy, but the underlying immune resistance remains incompletely defined. Here we integrate clinical outcome analyses, paired human tissue profiling and syngeneic mouse models to characterize the BrM immune microenvironment. Clinical analyses suggest improved intracranial disease control with nivolumab plus ipilimumab compared with nivolumab alone. Paired human specimens show that BrMs contain fewer cytotoxic T lymphocytes (CTLs) and tertiary lymphoid structures (TLSs) than primary tumors, defining an immune-excluded phenotype. A syngeneic BrM model recapitulates this phenotype and resists anti-PD-1 monotherapy, whereas combined anti-PD-1 and anti-CTLA-4 blockade suppresses tumor growth and prolongs survival. Single-cell RNA sequencing, flow cytometry and immunofluorescence show increased CTL infiltration and effector function after combination therapy. CD8+ T cell depletion abrogates therapeutic benefit, and combination therapy expands T follicular helper-like cells and induces TLS-like structures. These findings manifest increased adaptive immune response of dual checkpoint blockade in NSCLC BrMs.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper links to its data, not to its authors' code: see the Data section.
Code availability
No custom code was developed in this study. All analyses were performed using publicly available software and packages described in the Methods section.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE161116, at NCBI GEO; found in the text, “Public transcriptome analysis of paired…”
Data Availability Statement
Source data are provided with this paper. Raw single-cell RNA sequencing data have been deposited in the DDBJ database [https://
No custom code was developed in this study. All analyses were performed using publicly available software and packages described in the Methods section.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 23 authors, 3 keywords, 17 MeSH terms, 1 funder, 53 references.
Cite
This paper
Hosoya, K., Ozasa, H., Tsuji, T., Oi, M., Shima, Y., Suminaga, K., Hashimoto, K., Yoshida, H., Funazo, T., Ajimizu, H., Nomizo, T., Yoshida, H., Katsuragawa, H., Tsuji, K., Sano, N., Takada, S., Mineharu, Y., Nishikawa, S., Menju, T., . . . Hirai, T. (2026). Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8&
BibTeX
@article{hosoya2026anti,
author = {Hosoya, Kazutaka and Ozasa, Hiroaki and Tsuji, Takahiro and Oi, Masahiro and Shima, Yusuke and Suminaga, Keiichiro and Hashimoto, Kentaro and Yoshida, Hiroshi and Funazo, Tomoko and Ajimizu, Hitomi and Nomizo, Takashi and Yoshida, Hironori and Katsuragawa, Hiroyuki and Tsuji, Kentaro and Sano, Noritaka and Takada, Shigeki and Mineharu, Yohei and Nishikawa, Shigeto and Menju, Toshi and Yoshizawa, Akihiko and Arakawa, Yoshiki and Wake, Hiroaki and Hirai, Toyohiro},
title = {{Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8\&
journal = {Nature communications},
year = {2026},
month = jul,
volume = {17},
number = {1},
pages = {5681},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/
url = {https://
pmid = {42414284},
pmcid = {PMC13342341}
}
RIS
TY - JOUR
AU - Hosoya, Kazutaka
AU - Ozasa, Hiroaki
AU - Tsuji, Takahiro
AU - Oi, Masahiro
AU - Shima, Yusuke
AU - Suminaga, Keiichiro
AU - Hashimoto, Kentaro
AU - Yoshida, Hiroshi
AU - Funazo, Tomoko
AU - Ajimizu, Hitomi
AU - Nomizo, Takashi
AU - Yoshida, Hironori
AU - Katsuragawa, Hiroyuki
AU - Tsuji, Kentaro
AU - Sano, Noritaka
AU - Takada, Shigeki
AU - Mineharu, Yohei
AU - Nishikawa, Shigeto
AU - Menju, Toshi
AU - Yoshizawa, Akihiko
AU - Arakawa, Yoshiki
AU - Wake, Hiroaki
AU - Hirai, Toyohiro
TI - Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8&
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/
VL - 17
IS - 1
SP - 5681
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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