Endometrial Tumor Microenvironment Alters Human NK Cell Recruitment, and Resident NK Cell Phenotype and Function

Abstract

Endometrial Cancer is the most common cancer in the female genital tract in developed countries, and with its increasing incidence due to risk factors such as aging and obesity tends to become a public health issue. However, its immune environment has been less characterized than in other tumors such as breast cancers. NK cells are cytotoxic innate lymphoid cells that are considered as a major anti-tumoral effector cell type which function is drastically altered in tumors which participates to tumor progression. Here we characterize tumor NK cells both phenotypically and functionally in the tumor microenvironment of endometrial cancer. For that, we gathered endometrial tumors, tumor adjacent healthy tissue, blood from matching patients and healthy donor blood to perform comparative analysis of NK cells. First we found that NK cells were impoverished in the tumor infiltrate. We then compared the phenotype of NK cells in the tumor and found that tumor resident CD103 + NK cells exhibited more co-inhibitory molecules such as Tigit, and TIM-3 compared to recruited CD103 − NK cells and that the expression of these molecules increased with the severity of the disease. We showed that both chemokines (CXCL12, IP-10, and CCL27) and cytokines profiles (IL-1β and IL-6) were altered in the tumor microenvironment and might reduce NK cell function and recruitment to the tumor site. This led to hypothesize that the tumor microenvironment reduces resident NK cells cytotoxicity which we confirmed by measuring cytotoxic effector production and degranulation. Taken together, our results show that the tumor microenvironment reshapes NK cell phenotype and function to promote tumor progression.

TIGIT as an emerging immune checkpoint

“…Moreover, a strong correlation has been observed between TIGIT expression on peripheral blood CD8 + T cells and AML relapse post‐transplantation . In endometrial cancer, high levels of TIGIT on tumour‐resident NK cells have been associated with disease severity . Finally, a high TIGIT/DNAM‐1 ratio on tumour‐infiltrating T regs was shown to correlate with poor clinical outcome following ICB targeting PD‐1 and/or CTLA‐4 .…”

“…TIGIT up‐regulation has been observed in various malignancies, including melanoma, breast cancer, non‐small‐cell lung carcinoma (NSCLC), colon adenocarcinoma (COAD), gastric cancer, acute myeloid leukaemia (AML) and multiple myeloma (MM) . Many studies reported up‐regulated TIGIT expression on CD8 + T cells, but there are also descriptions of increased TIGIT levels on tumour‐infiltrating T regs and NK cells . In mouse pre‐clinical models and in cancer patients, TIGIT expression on tumour‐infiltrating CD8 + T cells often correlates with increased expression of other inhibitory receptors such as PD‐1, lymphocyte‐activation gene 3 (LAG‐3), T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3), and with decreased expression of DNAM‐1 .…”

“…In particular, TIGIT expression on CD8 + T cells in the peripheral blood of gastric cancer patients has been associated with decreased cellular metabolism which resulted in impaired proliferation, cytokine production and migration . Similar to TIGIT + CD8 + T cells, TIGIT + NK cells infiltrating mouse subcutaneous tumours or human endometrial cancers were found to co‐express other inhibitory receptors, such as LAG‐3 and TIM‐3 .…”

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Here, as well, blocking TIM-3 with antibodies increased NK cell cytotoxicity and cytokine secretion. Additional recent studies identified TIM-3 expression as a marker of NK cell dysfunction and disease severity in colorectal cancer, esophageal cancer, endometrial cancer, and bladder cancer (96,(98)(99)(100)(101). Interestingly, TIM-3 engagement was initially shown to increase the expression of IFN-γ by NK cells in response to galectin-9, the β-galactoside binding lectin (123).…”

Serum Chemokine-release Profiles in AML-patients Might Contribute to Predict the Clinical Course of the Disease

“…CXCL9 and CXCL10 are binding to CXC-chemokine receptor 3 on effector CD8 + T cells, T H 1 cells, and NK cells, thereby regulating their recruitment into tumors (Nagarsheth et al 2017). CXCL10, which is an important factor in NK cell-recruitment and NK cell-mediated lysis of tumor cells has been shown to be strongly produced in the tumor compared to the adjacent tissue, suggesting that an immune response is occurring in the tumor (Degos et al 2019). In various malignancies, CXCL9 and CXCL10 were reported to be produced predominantly by activated CD103 + dendritic cells, (tumor-associated) macrophages and tumor cells (Lieber et al 2018;Spranger et al 2017).…”