Studies show that endometrial cancer (EC) rates are increasing in younger people with obesity is a likely contributor to this observed proliferation because it raises estrogen production and adipokine release, which stimulates the production of endometrial cells.

Microenvironment

The tumor microenvironment plays an important role in both cancer progression and response to therapy. This microenvironment includes the supporting tissue and its interaction with the tumor, as well as the infiltrating immune cells (ie, the immunological tumor microenvironment [iTME]). Immunotherapy, therefore, has been considered as an alternative therapeutic pathway or an adjuvant to surgery depending on the subgroup EC being treated.

In the hopes of developing a more complete understanding of EC-infiltrating immune cells and their function within the iTME, Hannah van der Woude, PhD-candidate, and colleagues conducted a review study to assess the knowledge base of iTME and the potential of immunotherapies as a treatment of certain subgroups of EC. As van der Woude and colleagues stated in Frontiers in Oncology, “Here we aim to review the evidence describing the iTME of EC and how this may be influenced by increasing adiposity, discuss the successes and pitfalls of immunotherapies for EC treatment, and provide recommendations to fill the knowledge gaps that exist within the body of literature.”

Inconsistent Classification

The literature review posed some challenges due to the inconsistency of the classification system used to identify different subgroups of EC. The works examined typically used either a histological or a molecular subtype descriptor. Unfortunately, it is impossible to determine a histological subtype from a molecular subtype or vice versa. Therefore, the researchers found it difficult to interpret the role of infiltrating immune cell proportion and phenotype across the bodies of work examined. Although it would be costly, incorporating both histological and molecular classifications would be beneficial to future research.

Studies show that obesity is increasingly associated with EC; however, its connection with immunology is uncertain. van der Woude and colleagues found conflicting evidence regarding the significance of immune infiltration in patients with high BMI versus patients with low BMI. The mechanism of observed superior response to immunotherapy in patients with high BMI was also not conclusive.

The study team suggests that the clinical arsenal of immunotherapy in the treatment of EC could potentially be expanded through clinical trials focused on immunotherapies such as TIM-3 (ie, T-cell checkpoint that inhibits antitumor immunity) or the microphage-associated CD47-SIRPα pathway, which directly affects T-cell responses.

Novel Treatments

Although the importance of the iTME of EC is well documented across the body of literature reviewed, a complete understanding of the immune landscape of EC remains elusive. However, treatments such as levonorgestrel-releasing intrauterine system and immune checkpoint inhibitors continue to show promise as having direct impacts on the iTME. Further research into the immunological mechanisms of novel EC treatments could potentially open the door to a more personalized treatment approach.

van der Woude and colleagues expressed their hopes for this field of study, writing that “immunotherapies for adjuvant treatment of EC are still in their infancy and show promise for molecular subtypes characterized by high immune infiltration, but their use does not necessarily need to be restricted to such subtypes. A focus on characterizing the response to immunotherapies across the spectrum of subtypes is likely to yield important insight into their effectiveness in previously understudied subtypes.”

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