L.A. Tashireva

Characteristics of the immune microenvironment of endometrial cancer depending on the MMR status of the tumor

Objective. To study the microenvironment features of MMR-proficient (pMMR) and MMR-deficient (dMMR) endometrial cancer. Material and methods. The study included 34 patients with pMMR endometrial cancer and 10 patients with dMMR endometrial cancer. Using the method of multiplex TSA-associated (tyramide signal amplification) immunofluorescence, phenotyping of the tumor microenvironment was performed with an assessment of stromal and intratumor cell localization and PD-1 expression. Results. In pMMR endometrial tumors, the predominant cell population was CD163+ macrophages, and in tumors with dMMR, CD163+ macrophages were found equally with CD8+ T lymphocytes and CD20+ B lymphocytes. In dMMR tumors, the number of CD8+ T lymphocytes and CD20+ B lymphocytes (as well as CD20+ B lymphocytes expressing PD-1) is higher compared to pMMR tumors, while the number of FoxP3+ T lymphocytes was significantly lower. The number of CD163+ macrophages did not differ depending on the MMR status, while the number of CD163+ macrophages was higher in the stroma compared to the number of these cells located intraepithelially. In patients with dMMR tumors, the number of CD8+ T lymphocytes was higher in the stroma, and did not differ in pMMR tumors. Conclusion. In this study, it was found that dMMR endometrial tumors are characterized by an increase in the proportion of CD8+ T lymphocytes and CD20+ B lymphocytes, which may be associated with a better response to immunotherapy. The differences in spatial distribution of CD8+ T lymphocytes and CD163+ macrophages confirmed the importance of immune cell localization for prognosis and treatment efficacy. These results highlight the need for further study of the endometrial cancer microenvironment in order to personalize therapy.

Predicting Response to Immunotargeted Therapy in Endometrial Cancer via Tumor Immune Microenvironment: A Multicenter, Observational Study

Only one-third of patients with advanced MSS/pMMR endometrial cancer exhibit a lasting response to the combination treatment of Pembrolizumab and Lenvatinib. The combined administration of these two drugs is based on Lenvatinib’s ability to modulate the tumor microenvironment, enabling Pembrolizumab to exert its effect. These findings underscore the importance of exploring tumor microenvironment parameters to identify markers that can accurately select candidates for this type of therapy. An open non-randomized observational association study was conducted at six clinical centers, involving a total of 28 patients with advanced MSS/pMMR endometrial cancer who received Pembrolizumab and Lenvatinib therapy. Using TSA-associated multiplex immunofluorescence, we analyzed the proportion of CD8+ T lymphocytes, CD20+ B lymphocytes, FoxP3+ T regulatory lymphocytes, and CD163+ macrophages in tumor samples prior to immunotargeted therapy. The percentage of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio was significantly higher in patients who responded to treatment compared to non-responders (responders vs. non-responders: 0.24 (0.1–1.24)% vs. 0.08 (0.00–0.15)%, p = 0.0114; 1.44 (0.58–2.70) arb. unit vs. 19.00 (3.80–34.78) arb. unit, p = 0.0031). The sensitivity and specificity of these biomarkers were 85.71% and 70.59%, and 85.71% and 85.71%, respectively. The proportion of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio in the stroma of endometrial cancer serves as both a prognostic marker of response to immunotargeted therapy and a prognostic factor for progression-free survival in patients.