Endometrial cancer (EC), the fourth most common cancer in women, originates from the uterine epithelium (Rousset-Rouviere et al., 2021). Although the prevalence of EC increases in the postmenopausal period, 14% of EC patients are identified at the premenopausal age (Morice et al., 2016). As a result of aging and obesity, the incidence rate of EC is continuing to increase in Europe and North America (Morice et al., 2016). The risk factors associated with EC are divided into two groups, including epidemiological factors (diabetes, obesity, nulliparity, unopposed estrogen use, use of tamoxifen, early menarche, and late menopause) and genetic factors (Cowden syndrome, Lynch syndrome, and polymerase proofreading-associated polyposis) (Urick and Bell, 2019). Based on different histopathology, epidemiology, prognosis, and treatment, ECs are classified as type I and type II (Passarello et al., 2019). About 85% of ECs are type I with low-grade endometrioid morphology, which occur due to mutation in K-ras, PTEN, or MMR genes. This type is diploid, estrogen-dependent with good prognosis, low recurrence, and restricted to the uterus. Type II including serous and clear cell carcinomas, is associated with aneuploidy, p53 mutations, and over-expression of Her-2/neu. These tumors are more aggressive and diagnosed at the advanced stages (Passarello et al., 2019). Cytoreductive surgery, especially total hysterectomy, and salpingo-oophorectomy, are usually considered as treatment options for early-stage ECs; however, treatments for advanced-stage EC are still inadequate (Van Nyen et al., 2018). Therefore, investigations for improving our knowledge of genetic, molecular, and cellular mechanisms that influence the pathogenesis and prognosis of EC will allow for novel therapeutic and diagnostic targets to be identified.

The immune system guards against cancer pathogenesis by maintaining immune surveillance and homeostasis. Natural killer (NK) cells are important innate lymphoid cells that play role in immune surveillance and protect against the growth of tumor cells and virus-infected cells (Levy et al., 2011). They play a cytolytic activity by releasing interferon (IFN)-γ, granzymes, perforin, and other inflammatory cytokines. NK cells also recruit other immune cells to control the proliferation of cancer cells. There is a subset of NK cells in human decidua, known as uterine NK (uNK) cells or decidual NK (dNK) cells that increase during early pregnancy. They have a CD56superbright CD16− CD49a+ CD9+ phenotype and constitute about 50–70% of all feto-maternal interface lymphocytes in the first trimester of pregnancy. These cells act differently than peripheral NK cells (Bruno et al., 2020, Kumar et al., 2022). In cancer patients, there is a subset of NK cells that have characteristics in common with dNK cells and act as poorly cytotoxic proangiogenic NK cells. Several factors such as TGFβ, glycodelin-A, and hypoxia exist in different malignancies, such as breast, colon, endometrial and ovarian cancers, can “decidualize” NK cells. These cells are not able to control local tumor growth and metastasis (Bruno et al., 2020, Albini and Noonan, 2021). In addition, the function of NK cells is influenced by the balance between activating and inhibitory cell surface receptors. The killer cell Ig-like receptors (KIRs) are a family of receptors that are expressed on NK cells and control their development and function. They either inhibit or activate NK cells by interacting with classical and non-classical major histocompatibility complex (MHC) class I molecules (Pende et al., 2019). KIR receptors span 150 kb and are encoded by clustered genes on the leukocyte receptor complex (LRC) located on chromosome 19q13. The distinct feature of KIRs is the result of diversity in the KIR system, which is caused by individual-specific KIR gene content, allelic polymorphism, and variable expression of KIR repertoire content (Rajalingam, 2018). There are two groups of KIR haplotypes: group A with fixed gene content which expresses inhibitory KIR (iKIR) mostly and contains only one activating receptor KIR2DS4, while, group B has variable gene content and represents activating KIRs (aKIRs) predominantly. There are also framework/ pseudogenes (KIR3DL2, 2DL4, 3DP1, 3DL3) that exist in all KIR haplotypes (Pende et al., 2019, Rajalingam, 2012). Additionally, AA and Bx (AB and BB) genotypes were defined based on gene contents (Cooley et al., 2010). Bx genotypes were also divided into four subclasses (C4T4, CxTx, C4Tx and CxT4) according to the C4/T4 gene clusters. C4 and T4 gene clusters were determined considering linkage disequilibrium between certain KIR genes. The C4 cluster is located at the centromeric half, and the T4 cluster is located at the telomeric half of the KIR gene complex (Castrillon et al., 2022, Cooley et al., 2010).

It has been shown that specific KIR gene contents are associated with a wide range of diseases, such as cancer, infectious and autoimmune diseases. Thus, the present study was designed to investigate KIR genotype profiles, haplotypes, and clusters in confirmed cases of EC along with healthy controls to determine KIRs’ impact on susceptibility to EC in Iranians.