Nebot-Bral, L. | bioRxiv Science

bioRxiv2025

Glucocorticoids unleash immune-dependent melanoma control through inhibition of the GARP/TGF-β axis

Half of advanced melanoma patients fail to benefit from immune checkpoint blockade and novel treatments are urgently required. Testing topical medications used in other skin diseases for anti-cancer activity in an immunotherapy-resistant murine melanoma model, we counterintuitively found that glucocorticoids elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the glucocorticoid receptor in different cellular compartments revealed glucocorticoids acted not on immune cells but directly on tumor cells to downregulate expression of GARP (glycoprotein A repetitions predominant). This inhibited TGF-{beta} signaling and unleashed CTL killing. In agreement, glucocorticoids stimulated tumor control in multiple cancer models, but only if the tumors also responded to pharmacological inhibition of TGF-{beta} signaling. Furthermore, melanoma patients with high glucocorticoid receptor expression or signaling showed improved prognosis and lower TGF-{beta} signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF-{beta} axis emerges as a glucocorticoid-sensitive cancer cell-intrinsic immune evasive mechanism. SignificanceScreening widely used topical treatments in a melanoma model, this study uncovers a surprising role for glucocorticoids in triggering CD8+ T cell-dependent tumor control through downregulation of GARP and thus TGF-{beta} signaling. Melanoma patient sample analysis supported these findings suggesting GARP/TGF-{beta} activity functions as a tumor cell-intrinsic immune evasive mechanism, and GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy.

cancer biology↗

bioRxiv2024

Effect of MisMatch Repair Deficiency on metastasis occurrence modelized in a syngeneic mouse model

Mismatch repair deficiency leads to high mutation rates and microsatellite instability (MSI-H), associated with immune infiltration and responsiveness to immunotherapies. In early stages, MSI-H tumors generally have a better prognosis and lower metastatic potential than microsatellite-stable (MSS) tumors, especially in colorectal cancer. However, in advanced stages, MSI-H tumors lose this survival advantage for reasons that remain unclear. We developed a syngeneic mouse model of MSI cancer by knocking out the MMR gene Msh2 in the metastatic 4T1 breast cancer cell line. This model mirrored genomic features of MSI-H cancers and showed reduction in metastatic incidence compared to their MSS counterparts. In MSI-H tumors, we observed an enrichment of immune gene-signatures that negatively correlated with metastasis incidence. Importantly, a hybrid epithelial-mesenchymal signature, related to aggressiveness was detected only in metastatic MSI-H tumors which may explain the worse outcomes after recurrence of MSI tumors compared to MSS. Interestingly, we identified immature myeloid cells at primary and metastatic sites in MSI-H tumor-bearing mice, suggesting that MMR deficiency elicits specific immune responses beyond T-cell activation. SignificanceA novel syngeneic mouse model of MSI cancer demonstrates that the immune system regulates MSI cancer cell dissemination, offering an important tool to model advanced stages of human MSI-driven disease.

cancer biology↗