Causal role of 731 immune cells in endometrial cancer: a Mendelian randomization (MR) study

Abstract Background: Endometrial cancer (UCEC) is a prevalent malignancy in the field of gynecology worldwide. The development of UCEC involves various factors including tumor mutation burden (TMB) and the infiltration of immune cells. Nonetheless, our understanding of the precise impact of these immune cells on both anti-cancer immunity and the pathogenesis of endometrial cancer remains limited. Methods: In this study, we utilized a two-sample Mendelian randomization (MR) analysis to validate the causal relationship between immune cell markers and the risk of endometrial cancer. By employing publicly available genetic data, we thoroughly examined potential associations between 731 immune cell markers and the risk of endometrial cancer. Twenty-two million variants were identified from 731 immune cell signatures in 3,757 Sardinians, which were classified as median fluorescence intensity (MFI), relative cell count (RC), absolute cell count (AC), and morphological parameter (MP).In order to ensure the dependability and robustness of our findings, we performed a comprehensive sensitivity analysis to assess both heterogeneity and horizontal pleiotropy. Findings: In this investigation, the impact of endometrial cancer on immune phenotypes was explored using a two-sample casual analysis method, primarily employing the IVW technique. To ensure the reliability of the results, adjustments were made for multiple testing using the FDR approach. A total of 9 immunophenotypes were identified as being linked to the risk of endometrial cancer. Various validation methods, such as the MR-Egger method and the MR-ESTO method, were employed to verify these findings. Among the identified immune phenotypes, 4 were associated with an increased risk of endometrial cancer. These included SSC-A on HLA DR+ CD4+ T cell( β=1.054, 95% CI=1.004~1.107, P=0.034, PFDR = 0.050)、CD14- CD16- Absolute Count (β=1.006, 95% CI=1.000~1.012, P=0.036, PFDR = 0.049)、CD20 on IgD- CD24- B cell(β=1.042, 95% CI=1.008~1.076, P=0.014, PFDR = 0.047)、CD11c+ monocyte %monocyte(β=1.072, 95% CI=1.017~1.129, P=0.009, PFDR = 0.047). Notably, the association between CD11c+ monocyte %monocyte and the risk of endometrial cancer was particularly pronounced, with a 7.2% increase. On the other hand, 5 immune phenotypes showed a reduced risk of endometrial cancer, including CD25++ CD4+ T cell %T cell(β=0.095, 95% CI=0.913~0.999, P=0.047, PFDR = 0.049), CD27 on unswitched memory B cell(β=0.960, 95% CI=0.921~1.000, P=0.049, PFDR = 0.049), HLA DR on B cell(β=0.966, 95% CI=0.939~0.994, P=0.017, PFDR = 0.047), CD39+ CD4+ T cell %CD4+ T cell(β=0.956, 95% CI=0.917~0.997, P=0.035, PFDR = 0.049). While CD14- CD16- Absolute Count and CD25++ CD4+ T cell %T cell exhibited statistical significance, their effect sizes may not be substantial. Interestingly, CD27 on unswitched memory B cell displayed pleiotropic forms and biased estimates, ruling out the presence of horizontal pleiotropy and enhancing the credibility of the results. Conclusion: This research provides genetic evidence that supports the strong connection between immune cells and endometrial cancer, contributing to a deeper comprehension of the disease's pathogenesis.