The Causal Role of Immune Cells in Upper Gastrointestinal Cancers: A Mendelian Randomization (MR) Study

Objective: Upper gastrointestinal (UGI) cancers, particularly esophageal cancer (EC) and gastric cancer (GC), are significant global health concerns characterized by high morbidity and mortality rates.The role of the adaptive immune system in controlling the growth and recurrence of human UGI tumors remains controversial.Here, Mendelian randomization (MR) was employed to explore the causal relationship between immune cells and UGI cancers.Methods: An extensive two-sample MR analysis was enrolled in this study.Briefly, the publicly available genetic data were utilized for investigation of the causal relationship between 731 immune cells and various UGI cancers; the inverse variance weighted model and weighted medians were employed for MR analyses; and sensitivity analyses were adopted for heterogeneity and pleiotropy assessments.Results: Our analysis revealed a total of 20 immune cells associated with EC and 25 immune cells associated with GC.Of them, CD62L-HLA-DR++ monocytes, myeloid dendritic cell (DC) % DCs, CD20+ % B cells, CD4+ CD8dim % T lymphocytes, Naive double negative (DN) T cells (CD4-CD8-), CD4+ ACs, and SSC-A on CD14+ monocytes were strongly associated with EC; HLA-DR++ monocytes, IgD+CD24-lymphocytes, CD62L-HLA-DR++ monocyte ACs, and DN (CD4-CD8-) ACs were significantly correlated with GC.CD62L-HLA-DR++ cells were all correlated with all UGI cancers.Interestingly, CD62L-HLA-DR++ cells were negatively correlated with EC but positively correlated with GC.Conclusion: Our analysis for the relationships between immune cells and UGI cancers provides a framework for characterizing immune status and suggests a dynamic immune cell environment in the setting of UGI cancers.Our results also highlight multiple aspects of the immunosuppressive states found in UGI cancers, all of which may serve as promising potential new therapeutic targets.