| Title: |
TROP2/claudin program mediates immune exclusion to impede checkpoint blockade in breast cancer |
| Authors: |
Wu, Bogang; Thant, Win; Bitman, Elena; Liu, Ting; Liu, Jie; Paschalis, Eleftherios I; Patel, Bidish K; Nawrocki, Cole; Xu, Katherine H; Nieman, Linda T; Ting, David T; de Gois Macedo, Bruna; Cheng, Yang; Jiang, Kevin; Sun, Fengfei; Thimmiah, Nayana; Sun, Sheng; Abelman, Rachel O; Bossuyt, Veerle I; Isakoff, Steven J; Spring, Laura M; Bardia, Aditya; Ellisen, Leif W |
| Contributors: |
Congressionally Directed Medical Research Programs; National Cancer Institute |
| Source: |
Journal for ImmunoTherapy of Cancer ; volume 14, issue 4, page e012265 ; ISSN 2051-1426 |
| Publisher Information: |
BMJ |
| Publication Year: |
2026 |
| Description: |
Background Immune exclusion inhibits antitumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC. Methods We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-naïve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of trophoblast cell-surface antigen 2 (TROP2), a key target of anticancer antibody drug conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-programmed cell death protein 1 (PD-1) therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings. Results We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T-cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T-cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC sacituzumab govitecan, enhances the anti-PD-1 response and improves T-cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD-1 therapy in human breast cancer. Conclusions This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1136/jitc-2025-012265 |
| Availability: |
https://doi.org/10.1136/jitc-2025-012265; https://syndication.highwire.org/content/doi/10.1136/jitc-2025-012265 |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.F882AC90 |
| Database: |
BASE |