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CTLA-4 blockade enhances germinal center reactions in lymph nodes that drive glioma-specific IgG production and glioma clearance

ABSTRACT: Humoral immunity, which is mediated by B cells that mature in germinal centers (GCs) in lymph nodes (LNs), is essential for adaptive immune responses. However, the involvement of B cell responses in anti-tumor and immunotherapy responses remains largely unexplored. Here, we show that activation of B cells in GCs of tumor-draining deep cervical LNs (dcLNs) is necessary for the efficacy of CTLA-4 immune checkpoint blockade in glioma in vivo. We demonstrate that anti-CTLA-4 therapy enhances follicular helper T cell (Tfh) expansion in dcLNs, leading to GC B cell formation, class switching to IgG, and the generation of glioma-specific antibodies. Glioma-bearing mice lacking antibody-secreting cells did not benefit from CTLA-4 blockade. Furthermore, using our new in vivo reporter system, we show that distally-secreted glioma-specific IgG infiltrates the tumor microenvironment and triggers glioma cell phagocytosis. Our study uncovers a previously unknown B cell–dependent mechanism underlying anti-CTLA-4 mediated control of glioma, which could be harnessed to treat other tumor types.

ORGANISM(S): Mus musculus

PROVIDER: GSE315742 | GEO | 2026/05/28

REPOSITORIES: GEO

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CTLA-4 blockade enhances germinal center reactions in lymph nodes that drive glioma-specific IgG production and glioma clearance [scRNA/BCR-seq]

Project description:The orchestration of humoral immunity mediated by B cells in lymph nodes (LNs) is essential for generating adaptive immune response. Despite this crucial role in host defense, B cell responses in cancer have been primarily examined in the tumor microenvironment, while their role in LNs remains largely unexplored. We show that B cell responses in LNs induced by αCTLA-4 regulate glioblastoma (GBM) progression. αCTLA-4 promotes germinal center (GC) formation in deep cervical LNs by enhancing B cell–CD4 T cell interactions, leading to expansion of antigen-specific GC B cells and class switching. This generates tumor-specific IgG, which binds glioma cells and triggers antibody-mediated phagocytosis. Mice lacking antibody-secreting cells fail to benefit from CTLA-4 blockade, underscoring the importance of humoral immunity in tumor control. Our study highlights the role of B cells in tumor-draining LNs and uncovers a novel B cell–dependent mechanism underlying αCTLA-4 efficacy in GBM.

2026-05-28 | GSE293917 | GEO

CTLA-4 blockade enhances germinal center reactions in lymph nodes that drive glioma-specific IgG production and glioma clearance [bulk RNA-seq]

2026-05-28 | GSE293916 | GEO

Expression data from CD4+ and CD11c+ cells from DO11.10 RAG2-/- mice

Project description:Abatacept is a recombinant CTLA-4 moleculed fused to a mutated human IgG molecule, which is clinically used in rheumatoid arthritis by inhibiting CD28-costimulation. This study aimed to inverstigate the ability of abatacept -mediated costimulation blockade to induce antigen-specific tolerance during primary immune responses. This is important as some studies have suggested that costimulation blockade can lead to CD4+ T cell anergy which could be beneficial for early therapy of autoimmune diseases such as rheumatoid arthritis. In addition we also investigated the effect that abatacept has on CD11c+ antigen presenting cells. This is important as costimulation blocakde can affect the biderectional interaction between CD4+ T cells and CD11c+ cells influencing the immunological outcome. We used microarrays to identify if abatacept treatment leads to antigen specific anergy using transgenic animals and models of priming and oral tolerance that established a synchronised monoclonal response. In addition this magnified the effect on the CD11c+ antigen presenting cells. This study included 5 experimental groups. DO11.10 RAG2-/- mice have CD4+ T cells specific for the ovalbumin (OVA) peptide OVA323-339. These mice were immunised with CFA/OVA s.c. (primed group) or tolerised by feeding with OVA (50mg/kg) in the drinking water. CD4+ cells were isolated 10 days post immunisation from draining lymph nodes (LNs) of unimmunised (pooled LNs and Spleen), orally tolerised (mesenteric LNs), primed (axillary LNs), primed treated with control IgG (axillary LNs) and primed treated with abatacept (axillary LNs). For CD11c+ cells cells were isolated by pooled secondary lymphoid organs (LNs and spleen).

2014-10-07 | E-GEOD-62089 | biostudies-arrayexpress

Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade [WES]

Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.

2017-08-10 | GSE100808 | GEO

Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade [RNA-seq]

2017-08-10 | GSE100807 | GEO

Genetic Analysis of Tumor Samples

Project description:Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here we demonstrate that, based upon exome sequencing data, patients identified as non-responders to anti-CTLA-4 (ipilimumab) harbor a much higher genomic defects in the IFN-γ pathway genes than melanoma patients who had clinical response to ipilimumab therapy.

| phs001257 | dbGaP

Glioma-intrinsic MAPK/ERK signaling promotes immunotherapy efficacy through T cell infiltration and interferon responses

Project description:Glioblastoma (GBM) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) only showing efficacy in some patients, while the mechanisms governing therapeutic responsiveness are poorly defined. Although MAPK/ERK signaling correlates with survival following ICB, its causal role and mechanisms underlying tumor immunogenicity remain unclear. Here, we perform in vivo kinome-wide CRISPR/Cas9 screens in murine gliomas where we identify RAF-MEK-ERK axis as the strongest modulators of glioma susceptibility to anti-programmed cell death protein 1 (anti-PD-1) therapy and CD8+ T cell recognition. Experimentally-induced ERK phosphorylation (p-ERK) enhances survival after anti-PD-1 and anti-CLTA4, leading to durable antitumor immunity upon rechallenge. Additionally, glioma cell p-ERK promotes increased interferon responses and T cell infiltration. Notably, BRAF/MEK inhibition disrupts interferon programs and tumor-microglia interactions in BRAFV600E ex vivo in human GBM/brain slice cultures. Our findings elucidate that tumor-intrinsic MAPK/ERK promotes immunotherapy response, interferon responses, T cell tumor infiltration, and GBM cell-microglia interactions.

2026-05-21 | GSE331374 | GEO

Friends not foes: CTLA-4 blockade and mTOR inhibition cooperate during CD8+ T cell priming

Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory. Total RNA was isolated from FACS-sorted, antigen-specific CD8+T cells from different treatment conditions at 5 or 35 days after primary T cell activation

2015-01-31 | E-GEOD-63022 | biostudies-arrayexpress

Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking

Project description:Intracranial B16 melanoma tumors isolated from C57Bl6 mice were analyzed by mRNAseq. Four experimental groups were analyzed: (1) Mice with intracranial tumors receiving IgG; (2) Mice with intracranial tumors receiving anti-PD-1 plus anti-CTLA-4 therapy; (3) Mice with intracranial plus extracranial tumors receiving IgG; (4) Mice with intracranial plus extracranial tumors receiving anti-PD-1 plus anti-CTLA-4 therapy. Taggart et al., PNAS 2018;

2018-02-01 | GSE109485 | GEO

Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma

Project description:Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells. We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients. Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P = 0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neo-antigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.

| phs001041 | dbGaP

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