Clinicopathological Features of DLL3 Expression and T-Cell Infiltration in LCNEC: Insights From Pathology and Clinical Response to Tarlatamab.
4 affiliations
- 1Department of Respiratory Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
- 2Division of Molecular Pathology, Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
- 3Department of Thoracic Surgery, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
- 4Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Abstract
Background
Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive lung neuroendocrine neoplasm with poor prognosis. Recently, DLL3-targeted bispecific T-cell engagers (BiTEs) have shown promising efficacy in small cell lung cancer, and clinical trials are ongoing in LCNEC. This study evaluated DLL3 expression and CD8+ tumor-infiltrating lymphocytes (TILs) infiltration in LCNEC and investigated their clinical significance and association with tarlatamab efficacy.Methods
We retrospectively reviewed consecutive patients who were diagnosed with LCNEC. Immunohistochemical analyses for DLL3 and CD8 were performed. DLL3 positivity was defined as staining in ≥ 1% of tumor cells. CD8+ TIL infiltration was graded as low, moderate, or high.Results
Among 77 screened LCNEC cases, 44 were eligible for analysis. The median age was 75 years. DLL3 expression was observed in 70.5% of cases and was associated with worse survival. Low CD8+ TIL infiltration was observed in 59.1% of cases. Patients with high CD8+ TIL infiltration demonstrated significantly longer survival than those with low infiltration (p = 0.03). Among representative clinical cases, a patient with DLL3 (+)/CD8 TILs (-) LCNEC achieved marked tumor shrinkage, whereas a patient with DLL3 (-)/CD8 TILs (-) LCNEC showed no response.Conclusions
DLL3 is frequently expressed in LCNEC and correlates with a poorer prognosis. A majority of LCNEC cases are immunologically characterized as cold tumors lacking CD8+ TILs, which contributes to unfavorable clinical outcomes. Tarlatamab induced a robust antitumor response even in a DLL3 (+) cold tumor. DLL3-BiTE represents a promising therapeutic strategy for DLL3 (+) LCNEC.
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BibTeX
@article{kaneko2026clinicopathological,
title = {{Clinicopathological Features of DLL3 Expression and T-Cell Infiltration in LCNEC: Insights From Pathology and Clinical Response to Tarlatamab.}},
author = {Shotaro Kaneko and Naoki Furuya and Yoshihisa Sugiura and Hajime Tsuruoka and Kazuhiro Nishiyama and Honoka Morita and Tomoki Okura and Hisashi Saji and Junki Koike and Nobuyuki Ohike and Masamichi Mineshita},
journal = {Thoracic cancer},
year = {2026},
month = oct,
doi = {10.1111/1759-7714.70400},
url = {https://europepmc.org/article/MED/42876375},
note = {CC BY},
}
RIS
TY - JOUR
TI - Clinicopathological Features of DLL3 Expression and T-Cell Infiltration in LCNEC: Insights From Pathology and Clinical Response to Tarlatamab.
AU - Shotaro Kaneko
AU - Naoki Furuya
AU - Yoshihisa Sugiura
AU - Hajime Tsuruoka
AU - Kazuhiro Nishiyama
AU - Honoka Morita
AU - Tomoki Okura
AU - Hisashi Saji
AU - Junki Koike
AU - Nobuyuki Ohike
AU - Masamichi Mineshita
PY - 2026
DA - 2026/10/01
JO - Thoracic cancer
DO - 10.1111/1759-7714.70400
UR - https://europepmc.org/article/MED/42876375
AB - Background Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive lung neuroendocrine neoplasm with poor prognosis. Recently, DLL3-targeted bispecific T-cell engagers (BiTEs) have shown promising efficacy in small cell lung cancer, and clinical trials are ongoing in LCNEC. This study evaluated DLL3 expression and CD8+ tumor-infiltrating lymphocytes (TILs) infiltration in LCNEC and investigated their clinical significance and association with tarlatamab efficacy.Methods We retrospectively reviewed consecutive patients who were diagnosed with LCNEC. Immunohistochemical analyses for DLL3 and CD8 were performed. DLL3 positivity was defined as staining in ≥ 1% of tumor cells. CD8+ TIL infiltration was graded as low, moderate, or high.Results Among 77 screened LCNEC cases, 44 were eligible for analysis. The median age was 75 years. DLL3 expression was observed in 70.5% of cases and was associated with worse survival. Low CD8+ TIL infiltration was observed in 59.1% of cases. Patients with high CD8+ TIL infiltration demonstrated significantly longer survival than those with low infiltration (p = 0.03). Among representative clinical cases, a patient with DLL3 (+)/CD8 TILs (-) LCNEC achieved marked tumor shrinkage, whereas a patient with DLL3 (-)/CD8 TILs (-) LCNEC showed no response.Conclusions DLL3 is frequently expressed in LCNEC and correlates with a poorer prognosis. A majority of LCNEC cases are immunologically characterized as cold tumors lacking CD8+ TILs, which contributes to unfavorable clinical outcomes. Tarlatamab induced a robust antitumor response even in a DLL3 (+) cold tumor. DLL3-BiTE represents a promising therapeutic strategy for DLL3 (+) LCNEC.
SN - 1759-7706
SN - 1759-7714
ER -