Importance of the endometrial immune environment in endometrial cancer and associated therapies

Abstract

Endometrial cancer is rising in prevalence. The standard treatment modality of hysterectomy is becoming increasingly inadequate due primarily to the direct link between endometrial cancer and high BMI which increases surgical risks. This is an immunogenic cancer, with unique molecular subtypes associated with differential immune infiltration. Despite the immunogenicity of endometrial cancer, there is limited pre-clinical and clinical evidence of the function of immune cells in both the normal and cancerous endometrium. Immune checkpoint inhibitors for endometrial cancer are the most well studied type of immune therapy but these are not currently used as standard-of-care and importantly, they represent only one method of immune manipulation. There is limited evidence regarding the use of other immunotherapies as surgical adjuvants or alternatives. Levonorgestrel-loaded intra-uterine systems can also be effective for early-stage disease, but with varying success. There is currently no known reason as to what predisposes some patients to respond while others do not. As hormones can directly influence immune cell function, it is worth investigating the immune compartment in this context. This review assesses the immunological components of the endometrium and describes how the immune microenvironment changes with hormones, obesity, and in progression to malignancy. It also describes the importance of investigating novel pathways for immunotherapy.

Distribution of DC Subtypes: CD83+, DC-LAMP+, CD1a+, CD1c+, CD123+, and DC-SIGN+ in the Tumor Microenvironment of Endometrial Cancers—Correlation with Clinicopathologic Features

“…Endometrial cancer is considered immunogenic due to its selected molecular subtypes, especially POLE-ultramutated and MSI-hypermutated, which are associated with a high infiltration of inflammatory cells [21,22]. The positive impact of tumor-infiltrating immune cells on EC prognosis is well established, but the predictive abilities of particular immune subsets are more ambiguous [22]. Unified and holistic knowledge of the composition and functions of these subsets would facilitate the design of immunotherapy agents for EC treatment [21][22][23][24].…”

“…The positive impact of tumor-infiltrating immune cells on EC prognosis is well established, but the predictive abilities of particular immune subsets are more ambiguous [22]. Unified and holistic knowledge of the composition and functions of these subsets would facilitate the design of immunotherapy agents for EC treatment [21][22][23][24]. The role of dendritic cells in antitumor immunity has been exhaustively explored and is unargued in the context of recent findings [25][26][27][28][29].…”

“…Neoplasms trap dendritic cells by hindering their capabilities to travel to LNs and promoting apoptosis through FasL and TRAIL [30]. Other established mechanisms by which cancers influence DCs include natural killer cell (NK) inhibition (e.g., by tumor-delivered PGE2) [5,22]. NK cells produce CCL5 and XCL1, which act as chemoattractants for DCs, thereby contributing to their intratumoral accumulation.…”

“…The most common EC histological subtype is endometroid carcinoma, which accounts for up to 90% of cases [22]. It has a better prognosis than any other type, including clear cell (CCC), serous, and mucinous cancers [28].…”

Chasing Uterine Cancer with NK Cell-Based Immunotherapies

“…Notably, aging and obesity potentially alter the uterine or endometrial immune environment as both can induce chronic low-grade systemic inflammation [105][106][107][108][109]. Consequently, UC prevalence increases with aging and in females with obesity [110]. Thus, it becomes crucial to understand the EC immune microenvironment (ECIM or UCIM).…”