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Riluzole Enhancing anti-PD-1 Efficacy by Activating cGAS/STING Signaling

ABSTRACT: Colorectal cancer is the second leading cause of cancer mortality in the US. Although immune checkpoint blockade therapies such as anti-PD-1/PD-L1 have had successes in some patients, the response rate is still low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cGAS/STING pathway and increases expression of interferon β (IFNβ) and IFNβ-regulated genes including CXCL10. Inhibition of ATM, but not ATR, results in a synergistic increase in IFNβ expression, suggesting that riluzole-dependent double strand breaks contribute to cGAS/STING activation. Knockout of cGAS or STING significantly attenuated expression of IFNβ and CXCL10 and nearly abolished suppression of tumor growth. Riluzole failed to increase intratumoral CD8+ T cells in STING knockout tumors. These results indicate that riluzole recruits CD8+ T cells into the tumor microenvironment through tumor cell intrinsic STING activation. When riluzole was combined with a PD-1 antibody, the treatment was more effective in suppressing tumor growth in vivo. Taken together, our studies indicate that riluzole inhibits tumor growth through the activation of cGAS/STING signaling and may increase the efficacy of anti-PD-1/PD-L1 therapies in colon cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE251940 | GEO | 2024/09/27

REPOSITORIES: GEO

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Project description:Background: PD-1 pathway blockade has revolutionized cancer care, but many patients do not durably benefit from these therapies. Novel treatments to engage anti-tumor immunity in this setting are needed. The stimulator of interferon genes (STING) protein, an innate sensor of cytoplasmic DNA, is a promising target with several agonists in development; however, recent clinical trials of these agents have not demonstrated efficacy for most patients. Here, we present detailed biomarker analyses of a patient with anti-PD-L1 refractory Merkel cell carcinoma that had a durable (~1 year), abscopal response to ADU-S100 (intralesional STING agonist) combined with anti-PD-1 blockade. Methods: Tumor biopsies and peripheral blood acquired pre- and post-treatment were analyzed with single cell RNA sequencing, 27-color flow cytometry, T cell receptor sequencing and multiplexed immunohistochemistry (mIHC; post treatment tumor specimen only). Critically, cancer-specific CD8 T cells were identified using MHC-I tetramers containing peptides from the Merkel cell polyomavirus (MCPyV), the etiologic agent of this cancer. Cell lines and tumor specimens from 76 patients were used to evaluate STING expression and signaling in MCC. Results: High levels of antigen cancer-specific T cells were observed in the tumor prior to ADU-S100 treatment (12% of T cells recognized an MCPyV epitope). These cancer-specific CD8 T cells exhibited characteristics of exhaustion including high TOX and low TCF1. Following STING agonist treatment, MCPyV-specific CD8 T cells expanded 3-fold with minimal phenotypic changes. An increase in antigen presentation on MCC tumor cells was also observed (1.8% of tumor cells MHC-I positive before treatment, 8.2% after treatment). This was not a result of ADU-S100 acting directly on tumor cells as mIHC analysis of 88 tumor samples confirmed little or no STING expression in tumor cells, but high STING expression on infiltrating immune and stromal cells. Further in vitro studies showed MCPyV-positive MCC cell lines are STING deficient, and ADU-S100 did not induce interferon. Conclusions: Our study suggests that STING agonists act on intratumoral immune cells to release interferons, which upregulate tumor cell antigen presentation and reinvigorate the anti-tumor response from pre-existing cancer-specific T cells. Thus, patients with anti-PD-(L)1-refractory disease showing downregulation of antigen-presentation may benefit from intralesional STING agonists.

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Riluzole Enhancing anti-PD-1 Efficacy by Activating cGAS/STING Signaling

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