The Prognostic Value of Tumor-Infiltrating Immune Cells in Gynecologic Cancers

Abstract Immunotherapy has changed the standard of treatment for many cancers. However, only a small number of gynecologic cancer patients benefit from immunotherapy. The intra-tumoral immune landscapes are suggested as a predictor of the response to immunotherapies, but there are no studies that provide a comprehensive immune characterization for gynecologic cancers. To characterize cellular compositions of the immune infiltrates and investigate if the immune landscape is a predictor for patient prognosis in gynecologic cancers, we analyzed tumor immune infiltrates of ovarian cancer, cervical cancer, and uterine cancer from The Cancer Genome Atlas Program (TCGA) using QuanTIseq and EPIC. Ovarian cancer had the highest percentage of total immune cells. Cervical cancer and uterine corpus endometrial carcinoma have lower percentages of immune cells with 17% and 16%, respectively. Furthermore, ovarian cancer had a significantly higher monocyte and M2-liked macrophage percentage, but a lower percentage for CD8 T cells and neutrophils compared to cervical cancer and uterine cancer. Cervical cancer had the highest percentage for M1-liked macrophages and the lowest for CD4 T cells. Uterine cancer had the highest percentage of dendritic cells. In cervical cancer, higher cell infiltration of CD8 T-Cells and M2-liked macrophages was associated with a better prognosis. In uterine cancer, patients with a higher number of dendritic cells and CD8 T-Cells had significantly better clinical outcomes. However, higher CD4 T-cell infiltration was associated with a poor prognosis in uterine cancer. Interestingly, the patient survival was not affected by the infiltration of any individual immune cells which we analyzed in ovarian cancer. We identified and validated four immune subtypes associated with distinct immune cell infiltration in gynecologic cancers. Cervical and uterine cancer patients from an immune-desert subtype that had the least amount of lymphocyte infiltration and a high level of monocyte had the worst prognosis. By contrast, cervical and uterine cancer patients from an immune-warm subtype that had higher infiltration of CD8 T-cell, natural killer (NK) cells, and dendritic cells (DCs) had the best prognosis. However, the survival rate of ovarian cancer patients is similar among the four different subtypes. Our study provides a conceptual framework to understand the tumor immune microenvironment of different gynecologic cancers.