Causal relationship between cancer and immune cell traits: A two-sample mendelian randomization study.

Background: Observational studies provide evidence of correlations between cancer and the immune system. Previous research has established associations between immune traits and the propensity for developing certain cancers. However, a systematic exploration of these connections remains largely uncharted. Therefore, further investigation is needed to examine the causal association between cancer and immune cell traits using Mendelian randomization (MR) approach.

Methods: We identified genetic instruments for breast cancer (BC), lung cancer (LC), endometrial cancer (EC), ovarian cancer (OC), prostate cancer (PC), and their subtype cancers to investigate their potential causal impact on immune traits. Data on cancer and immune cell traits were obtained from the IEU Open GWAS project. To assess whether these five cancer types and subtype cancers have a causal association with immune cell traits, we conducted two-sample MR analyses. Additionally, we conducted bidirectional MR analyses to examine the direction of causal relationships and adjusted for potentially related pleiotropy through multivariable MR analysis.

Results: We have identified several causal relationships between different types of cancer and immune traits. We found that breast cancer may influence 49 immune cell traits, endometrial cancer may influence 38, lung cancer may influence 25, ovarian cancer may influence 19, and prostate cancer may influence 28. Among these, breast cancer and lung cancer were associated with four common immune traits: CD25 on IgD CD38, CD25 on sw mem, CD24 on IgD CD38, and CD25 on IgD CD38. Lung cancer and prostate cancer shared four immune traits: CD25 on IgD CD24, CD25 on IgD CD38, CD66b on CD66b myeloid cell, DN (CD4CD8) AC. Endometrial cancer and ovarian cancer shared two immune traits: TD DN (CD4CD8) %DN, EM DN (CD4CD8) %DN. Breast cancer and endometrial cancer shared one immune trait: CD20 on IgD CD38. Endometrial cancer and prostate cancer shared one immune trait: CCR2 on myeloid DC. Lastly, breast cancer, lung cancer, and prostate cancer shared one immune trait: CD25 on CD24 CD27. Additionally, we identified specific immune traits that may serve as protective or risk factors for cancers. We found 14 immune traits may influence breast cancer, 9 immune traits may influence endometrial cancer, 22 immune traits may influence lung cancer, 9 immune traits may influence ovarian cancer, and 14 immune traits may influence prostate cancer. Among these, breast cancer and prostate cancer shared three immune traits: HLA DR monocyte %monocyte, HLA DR on plasmacytoid DC, and HLA DR on DC. Lung cancer and ovarian cancer shared one immune trait: CD62L monocyte %monocyte. Prostate cancer and endometrial cancer shared one immune trait: HLA DR on CD33 HLA DR  CD11b. Lastly, ovarian cancer and prostate cancer shared one immune trait: CD3 on resting Treg.

Conclusions: Our MR study suggests a potential relationship between immune traits and cancers, particularly highlighting 14 immune traits that are simultaneously influenced by two or three of five cancer types, while also indicating that 6 immune traits may simultaneously contribute to the development of two of the cancers. This elucidation enables us to reveal a significant involvement of immune traits in cancer progression, providing critical insights into how immune traits affect cancer susceptibility.