AS778 - Immune-related markers, sex steroid hormones, and biliary tract cancers in men and women in the Biliary Tract Cancers Pooling Project (BiTCaPP)

Investigator Names and Contact Information

Sarah Jackson ()

Introduction/Intent

Biliary tract cancers include gallbladder (GBC), intrahepatic bile duct (IHBDC), extrahepatic bile duct (EHBDC). GBC has a female predominance with a worldwide female‐to‐male incidence rate ratio of 2:1. Conversely, incidence rates of IHBDC, EHBDC, and AVC are higher in men.^1,2 These sex disparities suggest that sex hormones may be involved in carcinogenesis. Several studies, including that of Jackson et al.3 conducted in the Biliary Tract Cancers Pooling Project (BiTCaPP), have shown that reproductive factors (proxies for endogenous hormone levels) among premenopausal women are associated with increased risks of GBC and IHBDC.3-13 In contrast, reproductive factors and exogenous sex hormones have not been associated with the risk of EHBDC in women.^3,14,15 We are currently assessing associations of circulating sex-steroid hormones and risk of GBC and EHBDC among older men and postmenopausal women (≥50 years of age) to directly evaluate the role of sex hormones (BRG 2021-0304) using samples from 13 cohorts in the Biliary Tract Cancers Pooling Project (BiTCaPP, see Table 1). Innate immunity is the body’s first line of defense characterized by macrophages, dendritic cells, natural killer (NK) cells, neutrophils, and eosinophils. In general, females mount a more robust innate immune response than males. The production of cytokines and chemokines by innate immune cells also differs between the sexes with the number of and function often differing between men and women.¹⁶ Sex steroid hormones can affect the recruitment and function of these immune cells, likely contributing to immune response differences between the sexes. Testosterone has an anti-inflammatory effect, and research has shown that testosterone dampens the cytokine responses.¹⁷ This may be why males have a diminished immune response to infection and vaccination.^16,17 Estrogen’s effects depend on the form (estradiol, estrone, etc.) and the dose (low level [physiological] or pregnancy related), cell type, sex, and receptor signaling pathways.18 Physiological estradiol enhances the pro-inflammatory capacity of macrophages and monocytes, whereas supraphysiological levels suppress the pro-inflammatory capacity. In contrast to estrogen, progesterone has an overall suppressive effect on innate immune cells.¹⁸ Biliary tract cancers are a good model for studying the role of inflammation in carcinogenesis given the highly inflammatory nature of its associated risk factors, in particular gallstones. However, the precise mechanisms linking inflammation and carcinogenesis remain unclear. Some studies have assessed immune markers and prognosis,^19-21 but few have evaluated the role of immune-related markers in biliary tract cancer development. To investigate the relation between sex hormones, immune-response, and biliary tract cancer risk, which might differ by sex, we propose to measure pre-diagnostic immune marker levels from the residual samples in the BiTCaPP circulating sex-steroid hormones project (BRG 2021-0304).

Specific Aims

1. To assess differences in associations of immune marker levels and cancer risk (GBC and EHBDC) between men and (postmenopausal) women ≥50 years of age
2. Assess the extent to which associations between inflammation-related conditions, such as obesity and diabetes, are mediated through inflammation, as measured by immune markers
3. Assess how sex steroid hormones levels (estradiol, estrone, progesterone, testosterone, dehydroepiandrosterone [DHEA], androstenedione, and dihydrotestosterone) mediate the association of immune response with cancer risk as measured by immune markers