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

Jiahui Wang; Yixin Kang; Yuxuan Li; Liang Sun; Jun Zhang; Senmi Qian; Ke Luo; Yi Jiang; Lichao Sun; Fangying Xu

doi:10.2147/JIR.S338584

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

J Inflamm Res. 2021 Nov 25:14:6223-6235. doi: 10.2147/JIR.S338584. eCollection 2021.

Authors

Jiahui Wang^#^{1

2}, Yixin Kang^#^{1

2}, Yuxuan Li^#^{1

2}, Liang Sun^{1

2}, Jun Zhang^{1

2}, Senmi Qian^{1

2}, Ke Luo¹, Yi Jiang³, Lichao Sun⁴, Fangying Xu^{1

2}

Affiliations

¹ Department of Pathology and Pathophysiology, and Department of General Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
² Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
³ Department of Statistics, School of Mathematical Sciences, Anhui University, Hefei, Anhui, People's Republic of China.
⁴ State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.

^# Contributed equally.

Abstract

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.

Keywords: colorectal cancer; gasdermin D; immune microenvironment; prognosis; pyroptosis.

Grants and funding

This work was supported by the grants of National Natural Science Foundation of China under Grant 81772570; the Open Projects of State Key Laboratory of Molecular Oncology (SKLMO-KF2021-17) and Program of Introducing Talents of Discipline to Universities under Grant B13026.