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Anti-VEGF treatment potentiates ICB responses through a BAFF and IL-12-dependent reprogramming of the TME

ABSTRACT: Anti-VEGF treatment has shown clinical activity in combination with checkpoint inhibitor therapy, but the exact mechanism is not known. We show that adding VEGF blockade to the ICB combination of anti-CTLA4 + anti-PD-L1 in cholangiocarcinoma unleashed a therapeutic efficacy driven through a novel multimodal mechanism dependent on BAFF production by T and myeloid cells, leading to a BAFF-dependent proinflammatory B cell response characterized by Germinal center B cell and plasma cell expansion, as well as IL-12 production. Using single cell RNA sequencing (scRNA-Seq) of paired pre- and post-treatment tumor biopsy samples from patients treated with anti-CTLA4, anti-PD-L1 and anti-VEGF, we characterized the treatment-associated immunological changes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284205 | GEO | 2025/03/16

REPOSITORIES: GEO

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B cell activating factor (BAFF) attenuates immunosuppressive monocytes in the melanoma tumor micro-environment

Project description:Emerging evidence indicates BAFF to be an important cytokine influencing anti-tumoral immunity. We generated a BAFF-overexpressing B16.F10 (BAFF) melanoma cell model and found that a significant survival advantage was conferred to C57BL/6 mice inoculated with BAFF cells. BAFF tumors had decreased myeloid infiltrates with lower PD-L1 expression. Monocyte depletion and anti-PD-L1 antibody treatment confirmed the functional significance on the phenotype. RNA-Seq analysis confirmed that monocytes isolated from BAFF tumors where characterized by a decreased exhaustive phenotype and enriched for in genes activating adaptive immune responses and NF- signaling. We wondered about the clinical relevance of BAFF plasma levels in melanoma patients. Evaluation of late stage metastatic melanoma patients treated with inhibitors of the PD-1/PD-L1 axis demonstrated a stratification of patients with high and low BAFF plasma levels, the former of which experienced lower responses to anti-PD-1 immunotherapies. In summary, we have shown that BAFF, through effects on tumor infiltrating monocytes not only impacts primary tumor growth but as biomarker can contribute to predicting response to anti-PD1 immunotherapy in later stages of advanced disease.

2022-08-31 | GSE179670 | GEO

Nanostring gene expression analysis of Tregs islated from Kdr KO versus transgene control SB1 tumors

Project description:Tumor-infiltrating Tregs were FACS sorted using their YFP signal from processed SB1 tumors implanted in Kdr(fl/fl)xFoxp3(yfp-cre) or Kdr(+/+)xFoxp3(yfp-cre) mice, fro which RNA was isolated for Nanostring analysis usig the Murine Cancer Immune Profiling Panel Anti-VEGF treatment has shown clinical activity in combination with checkpoint inhibitor therapy, but the exact mechanism is not known. We show that adding VEGF blockade to the ICB combination of anti-CTLA4 + anti-PD-L1 in cholangiocarcinoma unleashed a therapeutic efficacy driven through a novel multimodal mechanism dependent on BAFF production by T and myeloid cells, leading to a BAFF-dependent proinflammatory B cell response characterized by Germinal center B cell and plasma cell expansion, as well as IL-12 production. The mechanism culminates in a BAFF and IL-12-dependent expansion and rewiring of Tregs towards an anti-tumor Th-1-like fragile state. We translated this approach to the clinic with encouraging outcomes following an interim analysis of the first six CCA patients. Using paired PBMC, serum and tumor biopsy samples from patients treated with anti-CTLA4, anti-PD-L1 and anti-VEGF, we again observed treatmentassociated immunological changes characterized by Treg expansion and rewiring towards fragile and unstable states and a proinflammatory cytokine profile including elevated BAFF and IL-12 levels. Correlating immune changes with overall survival identified BAFF and IL-12 as potential biomarkers of treatment response. Finally, we explored the direct effect of VEGFR2 signaling on Treg transcriptional programming. Fragile and unstable Tregs showed diminished VEGF/VEGFR2 signaling. A mouse model genetically ablating VEGFR2 expression on Tregs led to diminished suppressive function and delayed tumor growth, an effect that was further enhanced by ICB therapy.

2025-03-14 | GSE285761 | GEO

Anti-VEGF treatment potentiates ICB responses through a BAFF and IL-12-dependent reprogramming of the TME

Project description:Anti-VEGF treatment potentiates ICB responses through a BAFF and IL-12-dependent reprogramming of the TME

| PRJNA1197972 | ENA

Radiation and Dual Checkpoint Blockade Activates Non-Redundant Mechanisms in Cancer

Project description:Response to immune checkpoint inhibitors may be improved through combinations with each other and other therapies, raising questions about non-redundancy and resistance. We report results from parallel studies of melanoma patients and mice treated with anti-CTLA4 and radiation (RT). Although combined treatment improved responses, resistance was common. Computational analyses of immune and transcriptomic profiles (provided here) revealed that resistance in mice was due to upregulation of tumor PD-L1 that drives T cell exhaustion. Accordingly, optimal response requires RT, anti-CTLA4, and anti-PD-L1. Anti-CTLA4 inhibits Tregs, RT diversifies and shapes the TCR repertoire, and anti-PD-L1 reinvigorates exhausted T cells. Together, all three therapies promote the expansion of clonotypes with distinct TCR traits. Similar to mice, patients with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response through distinct mechanisms.

2015-03-16 | GSE65503 | GEO

Anti-VEGF treatment enhances antitumor responses by targeting regulatory T cells

Project description:Cholangiocarcinoma (CCA) shows limited response to systemic treatments including immunotherapy. We initiated an open-label phase II clinical trial testing bevacizumab (anti-VEGF-A) plus tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-L1) in patients with primary liver cancer. Exceptional responses were observed in patients with CCA that were accompanied with moderate to severe, yet manageable immune-related events in the majority of patients. Correlative studies using paired PBMC and serum samples demonstrated a proinflammatory cytokine profile, reinvigoration of precursor exhausted CD8+ T cells, and expansion of regulatory T cell and non-classical monocyte subsets. We utilized subcutaneous, orthotopic as well as plasmid-induced murine CCA models to better understand how anti-VEGF-A enhances anti-tumor immunity induced by anti-CTLA4 plus anti-PD-L1. We describe a novel multi-modal mechanism of how anti-VEGF-A therapy enhances immune checkpoint inhibitor-induced immune responses. The treatment effect was dependent on an increase in tumor infiltrating B cells and IL-12 causing Treg rewiring towards fragile and unstable states. Using a mouse model that genetically ablates VEGFR2 expression on Tregs, we show that the VEGF /VEGFR2 axis on Tregs contributes to the pro-tumoral function of Tregs and supports tumor progression in a syngeneic CCA model. This study provides clinical evidence that simultaneously targeting three immunosuppressive axes, namely VEGF-A, CTLA-4 and PD-L1, can elicit strong anti-tumor immunity to potentiate CCA regression and merits broader evaluation in other cancers.

2025-03-14 | GSE249974 | GEO

RNAseq analysis of tumours from GEMMS animals to determine the effect of different aPDL1 combinations on lung tumours in situ

Project description:This study aims to identify combination treatments capable of inducing improved IO responses in lung tumours and thus, help guide decisions on the next combination arms for the HUDSON trial (post-IO). For that purpose, a lung tumour GEMM model was treated with either vehicle, PD-L1, ATR, ATR/PD-L1; Cisplatin/PD-L1/Ctla4 or VEGFR/PD-L1 and tumours collected for transcriptional profiling.

2024-01-29 | E-MTAB-13704 | biostudies-arrayexpress

BAFF engages distinct NFkappaB effectors in maturing and proliferating B cells

Project description:Identify genes which are induced in wild type B cells under antigenic stimuli, anti-IgM vs pro-survival stimuli, BAFF. Also find the differential expressed genes which are distinct from in co-stimulated conditions. RNAseq analysis of wild type primary B cells stimulated with anti-IgM alone, BAFF alone, or co-stimulated with both anti-IgM and BAFF for 8 and 30 hours

2015-02-01 | E-GEOD-54588 | biostudies-arrayexpress

Senescence prostate cancer cell promotes resistance to immune checkpoint blockade through ATR activation

Project description:Background: Checkpoint blockade immunotherapy represented by PD-1/PD-L1 or CTLA4 antibody treatment, has been of tremendous success for multiple cancers. Most patients with prostate cancer (PCa) either do not respond to CTLA4 immune checkpoint blockade or develop resistance to it, often because of low CTLA4 antigen presentation in cancer cells.

2025-04-02 | GSE234387 | GEO

Therapeutic Blocking of VEGF Binding to Neuropilin-2 Diminishes PD-L1 Expression to Activate Anti-Tumor Immunity in Prostate Cancer

Project description:Prostate cancers (PC) are largely unresponsive to immune checkpoint inhibitors and there is strong evidence that PD-L1 expression itself must be inhibited to activate anti-tumor immunity. Here, we report that neuropilin-2 (NRP2), which functions as a VEGF receptor on tumor cells, is an attractive target to activate anti-tumor immunity in prostate cancer because we demonstrate that VEGF/NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation in vitro. Inhibition of the binding of VEGF to NRP2 using a mouse specific anti-NRP2 mAb in a syngeneic model of prostate cancer that is resistant to checkpoint inhibition resulted in significant necrosis and tumor regression compared to both an anti-PD-L1 mAb and control IgG. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We also observed that the NRP2, VEGF-A, and VEGF-C genes are amplified in metastatic castration resistant and neuroendocrine prostate cancer (NEPC) and that NRP2high PD-L1high population in metastatic tumors had a significantly lower AR and higher NEPC scores than other populations. Therapeutic inhibition of VEGF binding to human NRP2 with a high affinity humanized mAb, which is suitable for clinical use, in organoids derived from NEPC patients also diminished PD-L1 expression and caused a significant increase in immune-mediated tumor cell killing consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this novel function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive primary and metastatic cancers, where blocking NRP2-VEGF signaling shows potential in mitigating the morbidity and mortality associated with these cancers.

2024-01-01 | GSE223811 | GEO

Post-ICB treatment PDAC infiltrating T cells TCR profile

Project description:For the subcutaneous model, 5x105 KPC-Luc cells were injected subcutaneously near the right flank of female C57BL/6 mice. 6-7 days after tumor implantation mice were randomized into 4 treatment groups and treatedwith VIP-R antagonist and/or anti-PD-1. While scram+IgG control mice received scrambled peptide and isotype IgG, the VIP-R antagonist, anti-PD-1 and VIP-R antagonist and anti-PD-1 groups received VIP-R antagonist and IgG; scrambled peptide and anti-PD-1; and VIP-R antagonist and anti-PD-1, respectively. The treatment regimen involved administering 10μg of scrambled or VIP-R antagonist: ANT008, subcutaneously every day and 200μg of IgG or anti-PD-1 intraperitoneally once every three days, for a total of 10 days.

2022-09-19 | GSE213482 | GEO

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