Gasdermin D in Different Subcellular Locations Predicts Diverse Progression, Immune Microenvironment and Prognosis in Colorectal Cancer

Background: Pyroptosis is a type of cell death that causes an immune reaction. Gasdermin D (GSDMD), as an executor of pyroptosis, has become an attractive target in cancer research. However, the clinical significance of GSDMD expression in different subcellular locations remains unclear. Methods: GSDMD was detected by immunohistochemistry in 178 cases of colorectal cancer with follow-up information. General data and information on systemic inflammatory indicators were collected from case records, and the clinicopathological parameters were reviewed by microscopy. CD3(+), CD4(+), and CD8 (+) T lymphocytes, CD20(+) B lymphocytes, and CD68(+) macrophages were detected by immunohistochemistry. Univariate survival analysis (Kaplan-Meier method, Log rank test) and a multivariate Cox proportional hazard model were used to analyze the impact of GSDMD on overall survival. Results: Survival analysis showed that high expression of cytoplasmic GSDMD was an independent favorable indicator for prognosis (P=0.027) and improved the efficacy of chemotherapy (P=0.012). Positive cytoplasmic GSDMD expression indicated lower probability of distant metastasis (P=0.024), yet nuclear GSDMD expression predicted deeper infiltration depth (P=0.007). Membranous GSDMD expression positively correlated with CD68(+) macrophages in tumor center (P=0.002) and CD8(+) lymphocytes in tumor invasive front (P=0.007). However, nuclear GSDMD was negatively related to CD68(+) macrophages in tumor invasive front (P<0.001) and CD8(+) lymphocytes in tumor center (P=0.069). Cytoplasmic GSDMD was associated with more CD3(+) lymphocytes both in tumor center (P=0.066) and tumor invasive front (P=0.008). Moreover, positive membranous GSDMD indicated a lower neutrophil-to-lymphocyte ratio (P=0.013). Conclusion: GSDMD subcellular localization patterns are related to CRC progression and immune reaction, and should be investigated in future studies.