Causal Relationship Between Immune Cells and Endometrial Cancer: A Two- Sample Mendelian Randomization Study

Abstract

Abstract Background In the context of endometrial cancer (EC), immune cells are pivotal in influencing tumor progression and outcome, exerting effects predominantly via mechanisms of immune surveillance, evasion, and infiltration into the tumor microenvironment. EC is classified, based on epidemiological data, conventional histopathology, and clinical behavior, into two primary subtypes: the estrogen-dependent endometrioid (type I) and the estrogen-independent non-endometrioid (type II) EC. Type II EC, though rarer, representing only 3 to 10% of all EC cases, is noteworthy for its aggressive clinical course, contributing to 39–44% of EC-related mortalities. In this evolving landscape, cancer immunotherapy has emerged as a promising avenue for treatment. However, there remains a critical need for further research to delineate the causal relationships between diverse immune cell phenotypes and endometrial cancer, as current literature lacks comprehensive insights into the specific roles and implications of these immune cell subsets in the pathophysiology of EC. Methods This study employs a comprehensive bidirectional Mendelian Randomization (MR) analysis to elucidate the interactions and causal relationships between immune cell characteristics and endometrial cancer risk. Mendelian Randomization is a robust research design that utilizes genetic variants as instrumental variables to investigate causal effects of exposure on observed outcomes. In our research, based on publicly available genetic data, we explored the bidirectional causality between 731 immune cell traits and the risk of endometrial cancer. Four immune characteristics were included: Median Fluorescence Intensity (MFI), Relative Cells (RC), Absolute Cells (AC), and Morphological Parameters (MP). Complementary MR approaches, such as the Inverse Variance Weighted (IVW) method, were employed, along with sensitivity analyses to assess the reliability of the outcomes. The meta-analysis was applied to assess the combined causal effect with multiple MR results. Results After Bonferroni Correction, three immune phenotypes showed significant association with type II (non-endometrioid) endometrial cancer: CD28 + CD45RA + CD8dim T cells (IVW: OR [95% CI]: 1.345 [1.175 to 1.539], p = 1.638E-5), CD45RA + CD28- CD8 + T cells (IVW: OR [95% CI]: 1.001 [1.0009 to 1.0014], p = 3.998E-16), and CD64 on CD14 + CD16 + monocytes (IVW: OR [95% CI]: 0.659 [0.539 to 0.807], p = 5.162E-5). Results from sensitivity analyses were consistent with the main findings. In a meta-analysis, it was demonstrated that, apart from non-endometrioid endometrial carcinoma, there is no causal association between other types of endometrial carcinoma (EC) and the genetically predicted immune cell phenotypes. Conclusions Our study, through genetic approaches, has established a close link between immune cells and non-endometrioid EC, thereby providing guidance for future clinical research.