Regulatory T cells, a subpopulation of suppressive T cells, are potent mediators of self-tolerance and essential for the suppression of triggered immune responses. The immune modulating capacity of these cells play a major role in both transplantation, autoimmune disease, allergy, cancer and pregnancy. During pregnancy, low numbers of regulatory T cells are associated with pregnancy failure and pregnancy complications such as pre-eclampsia. On the other hand, in cancer, low numbers of immunosuppressive T cells are correlated with better prognosis. Hence, maternal immune tolerance toward the fetus during pregnancy and the escape from host immunosurveillance by cancer seem to be based on similar immunological mechanisms being highly dependent on the balance between immune activation and suppression. As regulatory T cells hold a crucial role in several biological processes, they may also be promising subjects for therapeutic use. Especially in the field of cancer, cell therapy and checkpoint inhibitors have demonstrated that immune-based therapies have a very promising potential in treatment of human malignancies. However, these therapies are often accompanied by adverse autoimmune side effects. Therefore, expanding the knowledge to recognize the complexities of immune regulation pathways shared across different immunological scenarios is extremely important in order to improve and develop new strategies for immune-based therapy. The intent of this review is to highlight the functional characteristics of regulatory T cells in the context of mechanisms of immune regulation in pregnancy and cancer, and how manipulation of these mechanisms potentially may improve therapeutic options.

The potential role of human leukocyte antigen (HLA)-G as a target for new cancer immunotherapy drugs has increased the interest in the analysis of mechanisms by which HLA-G expression is regulated, and how the expression can be manipulated. We characterized HLA expression in breast cancer and malignant melanoma cell lines and investigated the induction of HLA-G expression by two distinct mechanisms: stimulation with interferon (IFN)-γ or inhibition of methylation by treatment with 5-aza-2’-deoxycytidine (5-aza-dC). The effect of IFN-γ and 5-aza-dC on HLA expression was dependent on the cancer cell lines studied. However, in general, surface expression of HLA class Ia was induced on all cell lines. Surface expression of HLA-G was inconclusive but induction of HLA-G mRNA was prevalent upon treatment with 5-aza-dC and a combination of IFN-γ and 5-aza-dC. IFN-γ alone failed to induce HLA-G expression in the HLA-G-negative cell lines. The results support that HLA-G expression is regulated partly by DNA methylation. Furthermore, IFN-γ may play a role in the maintenance of HLA-G expression rather than inducing expression. The study demonstrates the feasibility of manipulating HLA expression and contributes to the exploration of mechanisms that can be potential targets for immunotherapy in breast cancer and malignant melanoma.

Malignant melanoma is a highly immunogenic tumour, and the immune profile significantly influences cancer development and response to immunotherapy. The peripheral immune profile may identify high risk patients. The current study showed reduced levels of CD4⁺ T cells and increased levels of CD8⁺ T cells in peripheral blood from malignant melanoma patients compared with controls. Percentages of peripheral CD56^dimCD16⁺ NK cells were reduced and CD56^brightCD16⁻KIR3⁺ NK cells were increased in malignant melanoma patients. Late stage malignant melanoma was correlated with low levels of CD4⁺ T cells and high levels of CD56^brightCD16⁻KIR3⁺ NK cells. Finally, high levels of Tregs in peripheral blood were correlated with poor overall survival and disease-free survival. The results indicate that changes in specific immune cell subsets in peripheral blood samples from patients at the time of diagnosis may be potential biomarkers for prognosis and survival. Further studies will enable clarification of independent roles in tumour pathogenesis.

HLA‐F and HLA‐G may be involved in the pathogeneses of preeclampsia and fetal growth restriction (FGR). However, the functions of HLA‐F and HLA‐G in placental dysfunction remain unclear. The aim was to investigate differences in the prevalence of specific HLA‐F and HLA‐G gene allelic polymorphisms, genotypes, haplotypes, and diplotypes between controls and cases with preeclampsia or FGR. In total, blood samples from 365 pregnant females (controls, n = 192; preeclampsia, n = 164; FGR, n = 19) in their second and third trimester, and corresponding cordial blood samples (reflecting newborns, n = 160) were obtained after delivery. Genomic DNA was sequenced with a focus on the specific gene polymorphisms in the HLA‐F gene locus, especially the single nucleotide polymorphisms (SNPs) rs1362126 (G/A), rs2523405 (T/G) and rs2523393 (A/G), as well as the rs371194629 (14‐bp ins/del) in the 3′UTR of HLA‐G. Haplotype and diplotype distributions were obtained using PHASE v2.1, and linkage disequilibrium analyses were performed. SNPs in the HLA‐F gene locus and the 3′UTR of HLA‐G were not associated with the risk of preeclampsia or FGR. The SNPs did not correlate with fetal‐placental weight ratio, deviation of birth weight at gestational age, and placental weight. However, a trend towards an absence of certain HLA‐F‐HLA‐G extended diplotypes in preeclampsia was observed. The current study does not support associations of the investigated HLA‐F SNPs with preeclampsia or FGR. However, further studies are needed to evaluate the possible role of certain fetal HLA‐F‐HLA‐G extended haplotypes and diplotypes in preeclampsia.