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

Abstract

BackgroundPyroptosis 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.MethodsGSDMD 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.ResultsSurvival 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).ConclusionGSDMD subcellular localization patterns are related to CRC progression and immune reaction, and should be investigated in future studies.