Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CD40 agonism in renal cell carcinoma enhances immune checkpoint activity through myeloid cells

ABSTRACT: Immune checkpoint blockade (ICB) has improved survival for patients with metastatic renal cell carcinoma (RCC) but there remains a need to overcome resistance mechanisms. CD40 agonists increase anti-tumoral immunity, but limited data are available on their activity in RCC. We evaluated CD40 agonism in combination with ICB in preclinical RCC models. Adding CD40 agonism to anti-CTLA-4, but not anti-PD1, improved survival in Renca-bearing mice. CD40 agonism and anti-CTLA-4 upregulated CCL2, increased intra-tumoral macrophages and type 1 conventional dendritic cells (cDC1), whereas polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) decreased compared to control. Neutralizing CCL2 with CD40 agonism and CTLA-4 blockade partially abrogated the anti-tumoral effect and led to less increase of cDC1 and less decrease of PMN-MDSCs populations. Our studies suggest that CCL2 at least partially mediates the anti-tumoral effects of CD40 agonism, and more importantly, that the addition of CD40 agonism to ICB, particularly anti-CTLA-4, might be beneficial in RCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE333530 | GEO | 2026/06/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

scRNAseq of CD45+ cells within PDAC tumors treateted with CD40/ICB

Project description:Goal: determine how transcriptome of immune cells within the tumor microenvironment changes as a function of CD40 agonist and/or immune checkpoint blockade (anti-PD-1 AND anti-CTLA-4; "ICB") therapy

2020-05-10 | GSE150176 | GEO

IL-18 engineered to avoid decoy-receptor binding enhances tumor rejection by anti-CTLA-4 in kidney cancer models through immune microenvironment remodeling.

Project description:The cytokine interleukin-18 (IL-18) has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18’s anti-cancer efficacy. A “decoy-resistant” form of IL-18 (DR-18), that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential has recently been developed. Here, we investigate the therapeutic potential of DR-18 in renal cell carcinoma (RCC). We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intra-tumoral enrichment and clonal expansion of effector CD8+ T cells, decreased regulatory T cell levels, and enrichment of pro-inflammatory, anti-tumor myeloid cell populations, as assessed by scRNA- and scTCR-seq.

2024-11-01 | GSE279662 | GEO

Combined Flt3L and CD40 agonism restores dendritic cell driven T cell immunity in mouse models and patients with pancreatic cancer [mouse]

Project description:T cell directed immunotherapies have largely failed to demonstrate clinical efficacy in patients with pancreatic ductal adenocarcinoma (PDAC). This broad resistance may result from poor tumor antigenicity and an immunosuppressive tumor microenvironment (TME). We hypothesize that tumor immunity in pancreatic cancer patients is further limited by systemic and tumor-intrinsic suppression of conventional dendritic cells (cDC). Here, we find that low tissue expression of Flt3L may in part underly cDC deficits in PDAC tissues. We show in both autochthonous murine models and samples from a clinical trial, that treatment with systemic Flt3L and CD40 agonists can restore cDC number and function in the PDAC TME. Alone, CD40 agonism failed to fully engage cDC activity; yet when combined with Flt3L, the dual therapy triggered a cDC driven type-I immune response characterized by CD8+ T cell infiltration, interleukin-12 production, and a reciprocal interferon (IFN) response. In mice, type-1 cDCs (cDC1) were directly responsible for the influx of CD8+ T cells, which in-turn supported cDC1 survival via IFN-γ, resulting in a synergistic feed-forward loop. Lastly, while we find that combination Flt3L and CD40 agonism improve tumor immunity, they also increase the number and effector phenotype of FOXP3+ regulatory T cells (Tregs) in a process dependent on type-2 cDCs. Tregs were found to limit therapeutic efficacy by inhibiting mature cDC subsets, and concurrent Treg depletion led to improved tumor control. These data support the continued investigation of combined Flt3L and CD40. agonism, which represent a promising strategy to engage anti-tumor immunity in advanced human malignancies.

2025-06-20 | GSE283198 | GEO

Combined Flt3L and CD40 agonism restores dendritic cell driven T cell immunity in mouse models and patients with pancreatic cancer [human]

2025-06-20 | GSE283206 | GEO

Patient-derived xenograft platform for metastatic melanoma: RNA sequencing of 95 melanoma PDX samples

Project description:Although high clinical response rates are seen for immune checkpoint blockade (ICB) of metastatic melanoma, both intrinsic and acquired ICB resistance remain formidable challenges. Combination ICB shows improved clinical benefit, but is associated with severe adverse events and exceedingly high cost. Therefore, there is a dire need to stratify individual patients for their likelihood of responding to either anti-PD-1 or anti-CTLA-4 monotherapy, or the combination. Since it is conceivable that ICB responses are influenced by both tumor cell-intrinsic and stromal factors, we hypothesized that a predictive classifier ought to mirror both of these distinct features. We used a panel of melanoma patient-derived xenografts (PDX), in which human stromal cells upon transplantation are naturally replaced by their murine counterparts, to computationally subtract PDX RNA expression signals from those in patients’ melanomas. We thus derived both “Stromal immune” (SIM) and tumor cell-specific “Tumor-autonomous inflammation” (TAF) signatures. Here we report that the SIM signature predicts response to anti-CTLA-4 but not anti-PD-1 treatment, whereas the tumor TAF signature predicts response to anti-PD-1 but not anti-CTLA-4. Moreover, when used in conjunction, the signatures accurately predict response in two independent patient cohorts treated with the anti-CTLA-4 + anti-PD-1 combination. These signatures may be clinically exploited for personalized treatment advice based on the predicted benefit from either anti-CTLA-4 or anti-PD-1 monotherapy or their combination.

2020-04-27 | GSE129127 | GEO

Inhibiting B-cell-mediated Immunosuppression to Enhance the Immunotherapy Efficacy in Hepatocellular Carcinoma

Project description:Immunotherapy benefits only a minority of hepatocellular carcinoma (HCC) patients due to immune checkpoint blockade (ICB) resistance, and agonists of the stimulator of interferon genes (STING) also showed limited efficacy despite their immune-stimulating properties. Here we show that increased intratumoral B cells mediate the resistance to ICB and STING agonism. In the preclinical models with liver fibrosis that mimic human HCCs, tumors treated by anti-PD-1 ICB or a STING agonist (BMS-986301) showed more B-cell infiltration. STING agonism increased circulating IL-10 and intratumoral infiltration by B cells, including B cells expressing T-cell immunoglobulin and mucin domain 1 (TIM-1), and promoted the formation of tertiary lymphoid structure (TLS)-like structures, especially in the peritumoral areas. Strikingly, adding B cell depletion to ICB or STING agonism treatment significantly increased survival. Unlike ICB, STING agonism also had a pronounced anti-metastatic activity. In addition, the combination of STING agonism and TIM-1 blockade augmented B cell differentiation and antigen presentation in vitro and improved the anti-tumor effects in murine HCC in vivo. This approach decreased TIM-1+ B cells in the tumor and shifted B cells to higher expression of CD86 and MHC class II, enhancing their antigen presentation capability and further boosting the antitumor efficacy of CD8+ cytotoxic T cells. Our findings demonstrate that B cells are associated with ICB- and STING-mediated therapy resistance, and that depleting B cells or targeting TIM-1 enhances both innate and acquired therapeutic efficacy in HCC.

2025-10-26 | GSE301030 | GEO

Cancer immunotherapy via synergistic co-activation of myeloid cells [scRNA-seq]

Project description:The goal of this study was to define the impact of beta-glucan (CLEC7A agonist), anti-CD40 (agonist) and the combination of beta-glucan and anti-CD40 on the intra-tumoral immune landscape of mouse orthotopic pancreatic tumors using single-cell RNA sequencing.

2023-11-10 | GSE233171 | GEO

Whole Exome Predictors Immune Checkpoint Therapy Response in Renal Cell Carcinoma

Project description:<p>Immune checkpoint therapies, including monoclonal antibodies to programmed cell death-1 (PD-1) and cytotoxic % lymphocyte associated protein-4 (CTLA-4), yield durable clinical responses across many tumor types, including metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, predictors of response to these therapies in RCC are still unknown. Genomic characterization of large clinical cohorts of patients treated with anti-CTLA-4 and anti-PD-1 agents in melanoma and NSCLC have suggested that high mutational burden, high neoantigen burden, and high expression of certain genes in pre-treatment tumors may be associated with patient response to these therapies. In this study, we sought to investigate genomic predictors of response to anti-PD1 therapy in metastatic RCC in two independent clinical cohorts using whole exome and whole transcriptome sequencing.</p>

| phs001493 | dbGaP

PABPC1L promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in renal cell carcinoma

Project description:The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.

2024-02-14 | GSE241871 | GEO