Presence of regulatory T-cells in endometrial cancer predicts poorer overall survival and promotes progression of tumor cells

Abstract

Purpose Endometrial cancer (EC) is one of the most common gynaecologic malignancies. Tumor infiltrating regulatory T-cells (Treg) have been reported to have a prognostic impact in many malignancies. Immunotherapeutic strategies are gaining interest for advanced and recurrent EC cases, where treatment options are rare. Our study was aimed at determining the value of Treg in EC progression. Methods EC specimens from 275 patients and 28 controls were screened immunohistochemically for the presence of Treg represented by FoxP3. Correlations with clinicopathological and survival parameters were performed. Functional assays were performed using EC cell lines Ishikawa + and RL95-2 after co-culturing with isolated CD4 + CD25 + CD127dim Treg. To assess the influence of EC on the composition of peripheral blood mononuclear cells (PBMC), flow cytometric analyses were performed. Results We found that an increased infiltration of Treg was associated with high grades and a reduced overall survival. Treg were almost absent in endometrium tissues from healthy control patients. Co-culture of tumor cells with CD4 + CD25 + CD127dim Treg led to functional changes: enhanced invasion, migration and viability indicated that increased levels of Treg in the tumor microenvironment may promote tumor growth. Furthermore, we found that the presence of EC cells led to phenotypic changes in PBMC, showing significantly increased levels of CD25 and FoxP3. Conclusion Our results indicate that the presence of Treg in the EC tumor environment is associated with a poorer outcome. A remarkable impact of Treg on tumor cell behaviour and vice versa of tumor cells on PBMC subpopulations support this notion mechanistically. Our findings provide a basis for focusing on Treg as potential future therapeutic targets in EC.

Association between immune cells and endometrial cancer: A bidirectional Mendelian randomization study

“…[35] Zhi wei Zhai et al found in a study of colorectal cancer that the proportion of CD4 + CD45RA + T cells increased significantly after surgery, suggesting that they play an important role in tumor immunity and have a close relationship to tumor staging and prognosis. [36] Immune tolerance and immune response regulation are significantly aided by the cell surface receptor CD127; Hu Xiaoyu et al [37] Inflammation suppression of CD127 and its downstream STAT5 signaling pathway in monocytes, Thomas Kolben et al [38] found that CD4 + CD25 + CD127 Treg cells led to an increase in uterine enhanced invasion, migration and viability of EC cells, Using flow cytometry, Li Li et al examined the elevated proportion of peripheral blood bearing CD127 regulatory T cells in EC patients as a potential source of immune tolerance in EC. [39] We have shown that increased expression of CM CD4+ %T cells in mature-stage T cells promotes EC risk.…”

Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers

“…In 275 tumor specimens from patients with endometrial cancer, high FOXP3 expression was correlated with poor OS [ 93 ] . A similar observation was reported for patients with primary breast cancer, where T reg cells and CCL5 were co-expressed with standard prognostic markers for breast cancer [ 94 ] .…”

“…Third, an increase in T reg cells early in therapy may represent a mobilization of the T reg cells from the tumor tissue into the periphery and consequently have limited value for a prediction. Using in vitro co-cultures of peripheral blood mononuclear cells (PBMCs) from healthy volunteers, adding them to endometrial cancer cell lines led to an increase of T reg cells within a few hours, suggesting a prompt migratory response of T reg cells [ 93 ] . Hence, it is possible that once tumor cells are prevented from producing chemoattractant factors as a result of therapeutic intervention, T reg cells may migrate away from the tumor tissue and subsequently be detected in peripheral blood.…”

ZAP70 interaction with 13 mRNAs as a potential immunotherapeutic target for endometrial cancer

“…In addition to ZAP70, 13 other key genes were found to have been reported in normal endometrium or EC (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). Therefore, ZAP70 was selected for the subsequent experimental verification because to the best of our knowledge, it has not been reported in EC or endometrial tissue and thus represents a novel target.…”