Anti-vascular endothelial growth factor treatment potentiates immune checkpoint blockade through a BAFF- and IL-12-dependent reprogramming of the TME

Mohamed-Reda Benmebarek¹, Cihan Oguz², Matthias Seifert¹, Benjamin Ruf¹, Yuta Myojin¹, Kylynda C Bauer¹, Patrick Huang¹, Chi Ma¹, Marina Villamor-Payà³, Francisco Rodriguez-Matos¹, Marlaine Soliman¹, Rajiv Trehan¹, Cecilia Monge¹, Changqing Xie¹, David E Kleiner⁴, Bradford J Wood⁵, Elliot B Levy⁵, Anuradha Budhu⁶, Noemi Kedei⁷, Christian T Mayer⁸, Xin Wei Wang⁹, Justin Lack², William Telford⁴, Firouzeh Korangy¹, Tim F Greten¹⁰

Affiliations

¹ Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
² Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³ Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Center for Interventional Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ CCR Collaborative Bioinformatics Resource, Office of Science and Technology Resources, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁸ Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: tim.greten@nih.gov.

PMID: 40088889
PMCID: PMC11981852 (available on 2026-04-08)
DOI: 10.1016/j.immuni.2025.02.017

Anti-vascular endothelial growth factor treatment potentiates immune checkpoint blockade through a BAFF- and IL-12-dependent reprogramming of the TME

Mohamed-Reda Benmebarek et al. Immunity. 2025.

. 2025 Apr 8;58(4):926-945.e10.

doi: 10.1016/j.immuni.2025.02.017. Epub 2025 Mar 14.

Authors

Affiliations

¹ Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
² Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³ Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Center for Interventional Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ CCR Collaborative Bioinformatics Resource, Office of Science and Technology Resources, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁸ Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: tim.greten@nih.gov.

PMID: 40088889
PMCID: PMC11981852 (available on 2026-04-08)
DOI: 10.1016/j.immuni.2025.02.017

Abstract

Anti-vascular endothelial growth factor (VEGF) treatment has shown clinical activity together with immune checkpoint blockade (ICB), but the exact mechanism is not known. We show that VEGF blockade in combination with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) + anti-programmed death-ligand 1 (PD-L1) in cholangiocarcinoma (CCA) potentiated a multimodal mechanism dependent on B cell activating factor (BAFF), leading to a proinflammatory B cell response. It led to a BAFF- and interleukin (IL)-12-dependent expansion and rewiring of T regulatory cells (Tregs) toward an anti-tumor T helper-1 (Th-1)-like fragile state. We translated this approach to the clinic and observed immunological changes characterized by Treg cell expansion and rewiring toward fragile and unstable states. We explored the effect of VEGF receptor 2 (VEGFR2) signaling on Treg cell transcriptional programming and established a mouse model ablating VEGFR2 expression on Treg cells. This study reveals the immunological interplay resulting from targeting VEGF together with CTLA-4 and PD-L1 blockade.

Keywords: BAFF; CCA; ICB; TLSs; TME; Treg fragility; Tregs; cholangiocarcinoma; immune checkpoint blockade; regulatory T cells; tertiary lymphoid structures; tumor microenvironment.

Published by Elsevier Inc.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Greten TF, Schwabe R, Bardeesy N, Ma L, Goyal L, Kelley RK, and Wang XW (2023). Immunology and immunotherapy of cholangiocarcinoma. Nature Reviews Gastroenterology & Hepatology 20, 349–365. 10.1038/s41575-022-00741-4. - DOI - PubMed
1. Kitano Y, Okabe H, Yamashita YI, Nakagawa S, Saito Y, Umezaki N, Tsukamoto M, Yamao T, Yamamura K, Arima K, et al. (2018). Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer 118, 171–180. 10.1038/bjc.2017.401. - DOI - PMC - PubMed
1. Konishi D, Umeda Y, Yoshida K, Shigeyasu K, Yano S, Toji T, Takeda S, Yoshida R, Yasui K, Fuji T, et al. (2022). Regulatory T cells induce a suppressive immune milieu and promote lymph node metastasis in intrahepatic cholangiocarcinoma. British Journal of Cancer 127, 757–765. 10.1038/s41416-022-01838-y. - DOI - PMC - PubMed
1. Green BL, Myojin Y, Ma C, Ruf B, Ma L, Zhang Q, Rosato U, Qi J, Revsine M, Wabitsch S, et al. (2024). Immunosuppressive CD29(+) Treg accumulation in the liver in mice on checkpoint inhibitor therapy. Gut 73, 509–520. 10.1136/gutjnl-2023-330024. - DOI - PMC - PubMed
1. Ellis LM, and Hicklin DJ (2008). VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8, 579–591. 10.1038/nrc2403. - DOI - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Anti-vascular endothelial growth factor treatment potentiates immune checkpoint blockade through a BAFF- and IL-12-dependent reprogramming of the TME

Affiliations

Anti-vascular endothelial growth factor treatment potentiates immune checkpoint blockade through a BAFF- and IL-12-dependent reprogramming of the TME

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials