ABSTRACT
Tumor-associated macrophages (TAMs) are the main immune cells in the tumor microenvironment (TME) of endometrial cancer (EC). TAMs recruitment and polarization in EC is regulated by the TME of EC, culminating in a predominantly M2-like macrophage infiltration. TAMs promote lymphatic angiogenesis through cytokine secretion, aid immune escape of EC cells by synergizing with other immune cells, and contribute to the development of EC through secretion of exosomes so as to promoting EC development. EC is a hormone- and metabolism-dependent cancer, and TAMs promote EC through interactions on estrogen receptor (ER) and metabolic factors such as the metabolism of glucose, lipids, and amino acids. In addition, we have explored the predictive significance of some TAM-related indicators for EC prognosis, and TAMs show remarkable promise as a target for EC immunotherapy.
ABSTRACT
Endometrial cancer (EC) is an aggressive gynecological malignancy with an increased incidence rate. The immune landscape crucially affects immunotherapy efficacy and prognosis in EC patients. Here, we characterized the distinct tumor microenvironment signatures of EC tumors by analyzing single-cell RNA sequencing data from Gene Expression Omnibus and bulk RNA sequencing data from The Cancer Genome Atlas, which were compared with normal endometrium. Three macrophage subsets were identified, and two of them showed tissue-specific distribution. One of the macrophage subsets was dominant in macrophages derived from EC and exhibited characteristic behaviors such as promoting tumor growth and metastasis. One of the other macrophage subsets was mainly found in normal endometrium and served functions related to antigen presentation. We also identified a macrophage subset that was found in both EC and normal endometrial tissue. However, the pathway and cellular cross-talk of this subset were completely different based on the respective origin, suggesting a tumor-related differentiation mechanism of macrophages. Additionally, the tumor-enriched macrophage subset was found to predict immunotherapy responses in EC. Notably, we selected six genes from macrophage subset markers that could predict the survival of EC patients, SCL8A1, TXN, ANXA5, CST3, CD74 and NANS, and constructed a prognostic signature. To verify the signature, we identified immunohistochemistry for the tumor samples of 83 EC patients based on the selected genes and further followed up with the survival of the patients. Our results provide strong evidence that the signature can effectively predict the prognosis of EC patients.
Subject(s)
Endometrial Neoplasms , Female , Humans , Endometrial Neoplasms/genetics , Endometrial Neoplasms/therapy , Annexin A5 , Antigen Presentation , Cell Differentiation , Immunotherapy , Tumor MicroenvironmentABSTRACT
Various immunotherapies have demonstrated remarkable success over the past few decades, and have been approved for the treatment of different cancer types. However, patient responses to immunotherapy are variable, and approximately 50% of cases are refractory to these agents. Tumor biomarker-based stratification of cases may therefore help identify subpopulations that are sensitive/resistant to immunotherapy; it may also improve prediction of response in various cancers including gynecologic cancer. These biomarkers include the tumor mutational burden, microsatellite instability, mismatch repair deficiency, T cell-inflamed gene expression profile, programmed cell death protein 1 ligand 1, tumor-infiltrating lymphocytes, and numerous other genomic alterations. Future directions in the treatment of gynecologic cancer include the utilization of these biomarkers to select ideal candidates. This review focused on recent advances in the predictive ability of molecular biomarkers in patients with gynecologic cancer who undergo immunotherapy. The most recent developments in combined immunotherapy and targeted therapy strategies and novel immune interventions against gynecologic cancers have also been discussed.
