Problem: Several pregnancy complications have disparities based on the sex of the fetus. It is unknown whether the sex of the fetus differentially alters the maternal immune milieu, potentially contributing to the observed differences.Method of study: Using maternal plasma collected during 38 uncomplicated pregnancies (19 males, 19 females), we compared levels of cytokines, sex hormones, and angiogenic factors throughout gestation and postpartum.Results: Male fetal sex was associated with higher levels of proinflammatory cytokines (G‐CSF, IL‐12p70, IL‐21, and IL‐33) and angiogenic factors (PlGF and VEGF‐A) compared with female fetal sex at multiple timepoints. Female fetal sex was associated with higher levels of regulatory cytokines (IL‐5, IL‐9, IL‐17, and IL‐25). IL‐27 increased throughout pregnancy regardless of fetal sex. There was no fetal sex‐based difference in analyte concentrations at the postpartum measurement.Conclusion: Women carrying a male fetus exhibit a more proinflammatory/proangiogenic immune milieu than women carrying a female fetus.

Women diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma‐specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease. This is a retrospective population‐based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed from 1 January 1992 through 31 January 2011 with primary invasive cutaneous melanoma were included in our cohort. Melanoma‐specific survival was the main outcome studied. Of the 106,511 subjects that were included, 45% were female. Females in all age groups (18–45, 46–54, and ≥55) with localized and regional disease, were less likely to die from melanoma compared to males in the same age group. Among patients with localized and regional disease, the relative risk of death due to melanoma increased with advancing age at diagnosis; this increase was more pronounced among females than males. In contrast, we observed no female survival advantage among patients with distant disease and no effect of age on relative risk of death from melanoma. Females with localized and regional melanoma have a decreased risk of death compared to males within all age groups. Our data show no differences in survival between men and women with metastatic melanoma, indicating that the influence of sex on survival is limited to early stage disease but not confined to pre or perimenopausal age groups.

Problem: Pregnancy requires balance between tolerance to the haploidentical fetus and the mother's ability to mount immune responses. There are parallels to this phenomenon that occur in metastatic cancer. We assessed soluble program death ligand‐1 soluble PD‐L1 (sPD‐L1) and galectin‐9 in the blood of pregnant women during gestation as these molecules are highly involved in immune suppression during cancer.Method of study: Maternal blood was collected from 30 primigravida women at monthly intervals during pregnancy, delivery and 6‐week post‐partum. Blood was analyzed for sPD‐L1 and galectin‐9 concentrations by ELISA. Term placentas were collected in formalin and IHC was completed for PD‐L1 and galectin‐9 expression.Results: Maternal blood levels of sPD‐L1 (0.438 ng/mL) and galectin‐9 (1976 pg/mL) were elevated early in normal pregnancies compared to non‐pregnant controls (0.242 ng/mL and 773 pg/mL, respectively). sPD‐L1 increased throughout gestation, whereas galectin‐9 remained elevated until parturition; both proteins returned to control levels post‐partum. Women carrying male fetuses had significantly higher galectin‐9 levels, but not sPD‐L1, than those carrying females (2263 pg/mL vs 1874 pg/mL; P = .0005). Trophoblast cells of the term placenta coexpress galectin‐9 and PD‐L1.Conclusion: Immune‐regulatory molecules galectin‐9 and sPD‐L1 increased during pregnancy and may play a role in immune tolerance that is critical for the fetus.

Galectin-9, a β-galactoside-binding protein, is defined as a negative regulator of T helper 1 (Th1) immune responses, favoring Th2 bias. Systemic immunity in patients with metastatic melanoma is predominantly Th2 biased. We hypothesized that galectin-9 can modulate systemic immunity toward Th2 polarization in patients with advanced melanoma. The presence or concentration of galectin-9 was assessed in tumors and plasma, in patients with metastatic melanoma. The immunomodulatory function of galectin-9 was determined by exposing human peripheral blood mononuclear cells to galectin-9 in vitro. Galectin-9 was expressed in 57% of tumors and was significantly (3.6-fold) increased in the plasma of patients with advanced melanoma compared with healthy controls (P<0.001). High plasma galectin-9 concentration was associated with systemic Th2 polarization and reduced 2-year survival compared with low/no galectin-9 expression. In-vitro, galectin-9 reduced proliferation of healthy peripheral blood mononuclear cells, and promoted Th1 cell apoptosis, Th2-biased cell phenotypes, and cytokine secretion. Galectin-9 also stimulated monocyte differentiation toward an M2 macrophage phenotype, as assessed by chemokine/cytokine secretion and CD206 expression, observed both in vitro as well as in patients with metastatic melanoma. Elevated galectin-9 in patient plasma correlated with Th2 systemic bias and less favorable clinical outcomes for patients with metastatic melanoma. This Th2 bias appears to be not only a feature of the known mechanisms of Th1 apoptosis by T-cell immunoglobulin and mucin-domain containing-3 binding, but also mediated by myeloid cell differentiation toward an M2 phenotype, that favors tumor progression. These data support galectin-9 as a novel therapeutic target for patients with metastatic melanoma.

In 1989, one in four (25%) infants born to women living with HIV were infected; by the age of 2 years, there was 25% mortality among them due to HIV. These and other pieces of data prompted the development of interventions to offset vertical transmission, including the landmark Pediatric AIDS Clinical Trial Group Study (PACTG 076) in 1994. This study reported a 67.5% reduction in perinatal HIV transmission with prophylactic antenatal, intrapartum, and postnatal zidovudine. Numerous studies since then have provided compelling evidence to further optimize interventions, such that annual transmission rates of 0% are now reported by many health departments in the US and elimination has been validated in several countries around the world. Despite this success, the elimination of HIV’s vertical transmission on the global scale remains a work in progress, limited by socioeconomic factors such as the prohibitive cost of antiretrovirals. Here, we review some of the key trials underpinning the development of guidelines in the US as well as globally, and discuss the evidence through a historic lens.