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Impaired CD4+ T cell help through the CD40L-CD40 pathway contributes to reduced tumor control in males

ABSTRACT: Sex-based differences in cancer incidence are incompletely understood, but potential roles for the immune system are beginning to emerge. CD4+ T cells play a central role in organizing antitumor immunity. In addition to cytokine production, CD40L expression on CD4+ T cell provides necessary helper signaling to dendritic cells that is required for the priming of cytotoxic tumor-specific CD8+ T cells. Despite these critical functions, the impact of biological sex on the CD4+ T cell response to cancer remains unknown. Here, we demonstrate that impaired immune-mediated tumor control in male compared to female mice is driven by disparate helper CD4+ T cell responses between the sexes. We find that CD40L expression is reduced on CD4+ T cells isolated from males via a mechanism predominantly driven by sex hormones, resulting in decreased CD40 signaling in dendritic cells within tumor-draining lymph nodes. These deficits resulted in decreased helper CD4+ T cell frequencies and impaired CD8+ T cell function within the male tumor microenvironment which could be rescued by targeting the CD40L-CD40 axis. Our findings identify a novel mechanism of CD4+ T cell-based sex differences in the immune response to cancer that impairs tumor control.

ORGANISM(S): Mus musculus

PROVIDER: GSE305285 | GEO | 2026/03/06

REPOSITORIES: GEO

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Project description:Expression of CD40 in non-hematopoietic cells has been linked to inflammation. We presented evidence that CD40, a T-cell costimulatory molecule, is expressed in human Î²-cells and the engagement of CD40 in insulinoma cells activated the NFKB and ERK1/2 pathways. CD40 activation in human islets cells induced secretion of IL-8, MCP-1 and MIP-1 Î², which is abrogated by inhibitors of NFkB and ERK1/2 inhibitors. In this study, we have studied gene expression mediated by CD40-CD40L interaction in islet cells. This approach identified 90 genes and transcripts exhibiting at least a 1.7 fold increase in their expression intensity after treatment with soluble CD40L. A significant number of genes were related to inflammation and oxidative stress. We have a strong overexpression of CXCL1 (GroÎ±), CXCL2 (Mif2) and CXCL3; chemokines belonging to CXC family structurally related to Il-8. 11 genes were selected from this group and further quantified by Real Time PCR, including CXCL1. Activation of islet cells with CD40L induced the secretion of CXCL1 in a NFKB dependent manner. Engagement of CD40 in islet cells did not induce apoptosis, neither Î²-cell death and did not enhanced TNF-Î± mediated cell death as observed in insulinoma cells. CD40 activation in insulinoma cells, results in ERK1/2 dependent phsophorylation of synapsin I, a protein associated with the exocytosis machinery in neurons and Î²-cells. However, treatment of islets with soluble CD40L did not affect glucose induced insulin secretion. It has been reported that ductal cells always present in human islet preparations express CD40 constitutively (ref). We found that CD40-CD40L interaction in ductal cells, unlike in Î²-cells, induces secretion of diabetogenic cytokines IFNÎ³ and TNF-Î±. Furthermore, incubation of islets containing ductal cells with CD40L decreased Î²-cells viability as assessed by measurement of their mitochondrial membrane potential Experiment Overall Design: We isolated islet cells from three patients. Part of islet cells from each patient has been treated with CD40L. We compared gene expression in treated cells vs untreated for each patient using dye-swap.

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Impaired CD4+ T cell help through the CD40L-CD40 pathway contributes to reduced tumor control in males

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