GSDMD is associated with survival in human breast cancer but does not impact anti-tumor immunity in a mouse breast cancer model

Inflammation plays a pivotal role in cancer development, with chronic inflammation promoting tumour progression and treatment resistance, whereas acute inflammatory responses contribute to protective anti-tumour immunity. Gasdermin D (GSDMD) mediates the release of pro-inflammatory cytokines such as IL-1β. While the release of IL-1β is directly linked to the progression of several types of cancers, the role of GSDMD in cancer is less clear. In this study, the authors show that GSDMD expression is upregulated in human breast, kidney, liver, and prostate cancer. Higher GSDMD expression correlated with increased survival in primary breast invasive carcinoma (BRCA), but not in liver hepatocellular carcinoma (LIHC). In BRCA, but not in LIHC, high GSDMD expression correlated with a myeloid cell signature associated with improved prognosis. To further investigate the role of GSDMD in anticancer immunity, they induced breast cancer and hepatoma tumours in GSDMD-deficient mice. Contrary to their expectations, GSDMD deficiency had no effect on tumour growth, immune cell infiltration, or cytokine expression in the tumour microenvironment, except for Cxcl10 upregulation in hepatoma tumours. In vitro and in vivo innate immune activation with TLR ligands, that prime inflammatory responses, revealed no significant difference between GSDMD-deficient and wild-type mice. These results suggest that the impact of GSDMD on anticancer immunity is dependent on the tumour type. They underscore the complex role of inflammatory pathways in cancer, emphasizing the need for further exploration into the multifaceted effects of GSDMD in various tumour microenvironments. As several pharmacological modulators of GSDMD are available, this may lead to novel strategies for combination therapy in cancer.

Full article: https://doi.org/10.3389/fimmu.2024.1396777

This work was funded by the Swiss National Science Foundation, Rheumasearch Foundation and a generous donor advised by Carigest SA for financial support.

Why is it important?

This study investigates the role of Gasdermin D (GSDMD), a protein involved in inflammation, in cancer progression and immune response. GSDMD helps release pro-inflammatory molecules like IL-1β, known to influence cancer development. Researchers found that GSDMD expression is elevated in several cancers, including breast and liver cancer. Interestingly, high GSDMD expression in breast cancer correlated with better survival and a favourable immune cell profile, while no such link was seen in liver cancer. To further explore, GSDMD-deficient mice were used to induce breast and liver tumours. Surprisingly, the absence of GSDMD had little effect on tumour growth, immune infiltration, or cytokine levels. Techniques like RNA sequencing were employed to analyse GSDMD expression and immune cell infiltration in the tumour microenvironment, revealing that GSDMD’s role may vary by tumour type. These findings suggest a complex role for GSDMD in cancer, and its modulation could lead to new therapeutic strategies.

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