Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases.
Ontology highlight
ABSTRACT:
SUBMITTER: Milette S
PROVIDER: S-EPMC6917725 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
Publications
Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases.
Milette Simon S Hashimoto Masakazu M Perrino Stephanie S Qi Shu S Chen Michely M Ham Boram B Wang Ni N Istomine Roman R Lowy Andrew M AM Piccirillo Ciriaco A CA Brodt Pnina P
Nature communications 20191217 1
Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is rever ...[more]
Similar Datasets
Project description:Liver metastases (LM) remain a major cause of cancer-related death and are a major clinical challenge. LM and the female sex are predictors of a poorer response to immunotherapy but the underlying mechanisms remain unclear. We previously reported on a sexual dimorphism in the control of the tumor microenvironment (TME) of colorectal carcinoma liver metastases (CRCLM) and identified estrogen as a regulator of an immunosuppressive TME in the liver. Here we aimed to assess the effect of estrogen deprivation on the cytokine/chemokine profile associated with CRCLM, using a multiplex cytokine array and the RNAscope technology, and its effects on the innate and adaptive immune responses in the liver. We also evaluated the benefit of combining the selective estrogen-receptor degrader Fulvestrant with immune checkpoint blockade for the treatment of CRCLM. We show that estrogen depletion altered the cytokine/chemokine repertoire of the liver, decreased macrophage polarization, as reflected in reduced accumulation of tumor infiltrating M2 macrophages and increased the accumulation of CCL5+/CCR5+ CD8+ T and NKT cells in the liver TME. Similar results were obtained in a murine pancreatic ductal adenocarcinoma model. Importantly, treatment with Fulvestrant also increased the accumulation of CD8+CCL5+, CD8+CCR5+ T and NK cells in the liver TME and enhanced the therapeutic benefit of anti-PD1 immunotherapy, resulting in a significant reduction in the outgrowth of LM. Taken together, our results show that estrogen regulates immune cell recruitment to the liver and suggest that inhibition of estrogen action could potentiate the tumor-inhibitory effect of immunotherapy in hormone-independent and immunotherapy-resistant metastatic cancer.SignificanceThe immune microenvironment of the liver plays a major role in controlling the expansion of hepatic metastases and is regulated by estrogen. We show that treatment of tumor-bearing mice with an estrogen receptor degrader potentiated an anti-metastatic effect of immunotherapy. Our results provide mechanistic insight into clinical findings and a rationale for evaluating the efficacy of combination anti-estrogen and immunotherapy for prevention and/or treatment of hepatic metastases in female patients.
| S-EPMC11306998 | biostudies-literature
Project description:Sexual dimorphism affects various aspects of physiology, metabolism and longevity. Circadian clock is a master regulator of metabolism. Anti-aging dietary interventions reprogram circadian transcriptome in the liver and other tissues, but little is known about sexual dimorphism of circadian transcriptome. We compared circadian transcriptomes in the liver of male and female mice on ad libitum (AL) and 30% caloric restriction (CR) diets. We found that AL female mice had a larger number of oscillating genes than male mice, and the portion of the transcriptome with sex-specific rhythms displayed phase difference. We found that CR increased the number of oscillating genes in both sexes and strongly synchronized the transcriptome without complete elimination of sex dimorphism in rhythms. Sex also had an effect on the response of the rhythms to CR. Gene ontology analysis revealed sex-specific signatures in metabolic pathways, which suggests a complex interaction of sex, circadian rhythms, and diet.
| S-EPMC10973666 | biostudies-literature
Project description:Sex-specific physiology is commonly reported in animals, often indicating lower immune indices and higher oxidative stress in males than in females. Sexual selection is argued to explain these differences, but empirical evidence is limited. Here, we explore sex differences in immunity, oxidative physiology and packed cell volume of wild, adult, breeding birds (97 species, 1997 individuals, 14 230 physiological measurements). We show that higher female immune indices are most common across birds (when bias is present), but oxidative physiology shows no general sex-bias and packed cell volume is generally male-biased. In contrast with predictions based on sexual selection, male-biased sexual size dimorphism is associated with male-biased immune measures. Sexual dichromatism, mating system and parental roles had no effect on sex-specificity in physiology. Importantly, female-biased immunity remained after accounting for sexual selection indices. We conclude that cross-species differences in physiological sex-bias are largely unrelated to sexual selection and alternative explanations should be explored.
| S-EPMC9305230 | biostudies-literature
Project description:Sexual dimorphism in immune function is a common pattern in vertebrates and also in a number of invertebrates. Most often, females are more 'immunocompetent' than males. The underlying causes are explained by either the role of immunosuppressive substances, such as testosterone, or by fundamental differences in male and female life histories. Here, we investigate some of the main predictions of the immunocompetence handicap hypothesis (ICHH) in a comparative framework using mammals. We focus specifically on the prediction that measures of sexual competition across species explain the observed patterns of variation in sex-specific immunocompetence within species. Our results are not consistent with the ICHH, but we do find that female mammals tend to have higher white blood cell counts (WBC), with some further associations between cell counts and longevity in females. We also document positive covariance between sexual dimorphism in immunity, as measured by a subset of WBC, and dimorphism in the duration of effective breeding. This is consistent with the application of 'Bateman's principle' to immunity, with females maximizing fitness by lengthening lifespan through greater investment in immune defences. Moreover, we present a meta-analysis of insect immunity, as the lack of testosterone in insects provides a means to investigate Bateman's principle for immunity independently of the ICHH. Here, we also find a systematic female bias in the expression of one of the two components of insect immune function that we investigated (phenoloxidase). From these analyses, we conclude that the mechanistic explanations of the ICHH lack empirical support. Instead, fitness-related differences between the sexes are potentially sufficient to explain many natural patterns in immunocompetence.
| S-EPMC2666693 | biostudies-literature
Project description:Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune phenotypes can be visualized at https://immune-aging.jax.org to provide insights into future studies.
| S-EPMC7005316 | biostudies-literature
Project description:Purpose: To conduct a transcriptomic study of gene oscillations in mouse liver by RNA sequencing of total RNA samples from 6 different time points across the day. Specific interest is to see whether sex is a factor in large scale gene oscillations under ad-libitum control conditions and in response to caloric restriction diet, since caloric restriction was previously reported to affect gene oscillation Methods: Total RNA was isolated from 20 mg mouse liver tissue using mini spin column QIAGEN RNeasy Mini Kit (Ref #74104, Lot#163035346, Hilden, Germany) according to the manufacturer’s protocol. Sample purity was checked on Nano Drop 2000 (Thermo Fisher Scientific, Waltham, MA, USA) with 260/280 ratio ≥ 2.0 and 260/230 ratio ≥ 2.0 for every sample. Each sample used for the analysis had RNA integrity number > 7. The RNA sequencing was performed by Novogene Corporation Inc (Sacramento, CA, USA). After sample quality control, non-directional – polyA enrichment library was prepared using NEBNext Ultra™ II RNA Library Prep Kit for Illumina, and 50M reads (150bp, paired end) per sample were generated on Illumina NovaSeq 6000 platform. RNA-seq reads were mapped to the mouse protein coding genes (Ensembl: Mus_musculus; GRCm38) using Bowtie allowing up to 2-mismatches. The gene expected read counts and Transcripts Per Million (TPM) were estimated by RSEM (v1.2.3). The TPMs were further normalized by EBSeq R package to correct potential batch effect. Results: We have performed RNA sequencing analysis of mouse livers on Ad-libitum and timed Caloric Restriction diet across 6 time points in 24h. The results of subsequent compareRhythms analysis (R package) revealed that circadian rhythms in total RNA liver transcriptome are different between sexes of mice in both the number of oscillating genes and phase under ad-libitum diet. Caloric restriction increased the number of oscillating genes in both sexes and resulted in a larger overlap of rhythmic transcriptome between sexes, but did not eliminate the difference completely. The response of transcriptome to caloric restriction in terms of gain or loss of rhythm in gene expression profiles was also different between sexes. Additionally, we have shown that the lack of data stratification by sex might result in the failure to detect rhythmic changes in expression of some genes. Conclusions: Our study represents the first systematic analysis of the effect of sex on circadian rhythms of liver transcriptome under ad libitum and caloric restriction diets. We have shown that sex based differences exist in rhythmic transcriptome, as well as in the response of rhythmic transcriptome to diet. We are providing the data useful for both circadian and metabolic researchers and point out the gene candidates which may not be identified as rhythmic, if the data is not stratified by sex. With the help of GO analysis we have concluded that sex also influences the preference towards different processes to be regulated in rhythmic manner on transcriptional level - fatty acid metabolism and protein transport in males vs nucleic acid metabolism and RNA processing in females on ad-libitum diet. On calorie-restricted diet nucleic acid metabolism and RNA processing were enriched in males vs protein transport and signal transduction in females on calorie-restricted diet. These findings highlight a complex interaction of sex and diet in their effect on circadian rhythms in liver gene expression. All of the data from sequenced RNA samples from MALE liver were previously uploaded with the GSE211975 dataset. The current dataset only contains RNA-seq samples from FEMALE liver.
2023-03-01 | GSE216416 | GEO
Project description:Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor ?-deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases.
| S-EPMC4811157 | biostudies-literature
Project description:Sexual dimorphism in the mammalian immune system is manifested as more frequent and severe infectious diseases in males and, on the other hand, higher rates of autoimmune disease in females, yet insights underlying those differences are still lacking. Here we characterize sex differences in the immune system by RNA and ATAC sequence profiling of untreated and interferon-induced immune cell types in male and female mice. We detect very few differentially expressed genes between male and female immune cells except in macrophages from three different tissues. Accordingly, very few genomic regions display differences in accessibility between sexes. Transcriptional sexual dimorphism in macrophages is mediated by genes of innate immune pathways, and increases after interferon stimulation. Thus, the stronger immune response of females may be due to more activated innate immune pathways prior to pathogen invasion.
| S-EPMC6754408 | biostudies-literature
Project description:BackgroundLiver metastases are a major contributor to the poor immunotherapy response in colorectal cancer patients. However, the distinctions in the immune microenvironment between primary tumors and liver metastases are poorly characterized. The goal of this study was to compare the expression profile of multiple immune cells to further analyze the similarities and differences between the microenvironments of liver metastases and the primary tumor.MethodsTissues from 17 patients with colorectal cancer who underwent resection of primary and liver metastases was analyzed using multispectral immunofluorescence. The expression of multiple immune cells (CD8, Foxp3, CD68, CD163, CD20, CD11c, CD66b, CD56, PD-L1, INF-γ, Ki67 and VEGFR-2) in the tumor center (TC), tumor invasive front (< 150 µm from the tumor center, TF) and peritumoral region (≥ 150 µm from the tumor center, PT) was evaluated via comparison. The expression of CD68 and CD163 in different regions was further analyzed based on the cell colocalization method. In addition, different immune phenotypes were studied and compared according to the degree of CD8 infiltration.ResultsThe expression trends of 12 markers in the TF and TC regions were basically the same in the primary tumor and liver metastasis lesions. However, in comparison of the TF and PT regions, the expression trends were not identical between primary and liver metastases, especially CD163, which was more highly expressed in the PT region relative to the TF region. In the contrast of different space distribution, the expression of CD163 was higher in liver metastases than in the primary foci. Further analysis of CD68 and CD163 via colocalization revealed that the distribution of macrophages in liver metastases was significantly different from that in the primary foci, with CD68-CD163+ macrophages predominating in liver metastases. In addition, among the three immunophenotypes, CD163 expression was highest in the immune rejection phenotype.ConclusionsThe immune cells found in the primary tumors of colorectal cancer differed from those in liver metastases in terms of their spatial distribution. More immunosuppressive cells were present in the liver metastases, with the most pronounced differential distribution found for macrophages. CD68-CD163+ macrophages may be associated with intrahepatic immunosuppression and weak immunotherapeutic effects.
| S-EPMC9533561 | biostudies-literature
Project description:BackgroundSexual dimorphism in brain size is common among primates, including humans, apes and some Old World monkeys. In these species, the brain size of males is generally larger than that of females. Curiously, this dimorphism has persisted over the course of primate evolution and human origin, but there is no explanation for the underlying genetic controls that have maintained this disparity in brain size.ResultsIn the present study, we tested the effect of the female hormone (estradiol) on seven genes known to be related to brain size in both humans and nonhuman primates, and we identified half estrogen responsive elements (half EREs) in the promoter regions of four genes (MCPH1, ASPM, CDK5RAP2 and WDR62). Likewise, at sequence level, it appears that these half EREs are generally conserved across primates. Later testing via a reporter gene assay and cell-based endogenous expression measurement revealed that estradiol could significantly suppress the expression of the four affected genes involved in brain size. More intriguingly, when the half EREs were deleted from the promoters, the suppression effect disappeared, suggesting that the half EREs mediate the regulation of estradiol on the brain size genes. We next replicated these experiments using promoter sequences from chimpanzees and rhesus macaques, and observed a similar suppressive effect of estradiol on gene expression, suggesting that this mechanism is conserved among primate species that exhibit brain size dimorphism.ConclusionsBrain size dimorphism among certain primates, including humans, is likely regulated by estrogen through its sex-dependent suppression of brain size genes during development.
| S-EPMC4487212 | biostudies-literature