Preterm birth is widespread and causes 35% of all neonatal deaths. Infants who survive face potential long-term complications. A major contributing factor of preterm birth is infection. We investigated the role of interleukin 22 (IL22) as a potential clinically relevant cytokine during gestational infection. IL22 is an effector molecule secreted by immune cells. While the expression of IL22 was reported in normal nonpregnant endometrium and early pregnancy decidua, little is known about uterine IL22 expression during mid or late gestational stages of pregnancy. Since IL22 has been shown to be an essential mediator in epithelial regeneration and wound repair, we investigated the potential role of IL22 during defense against an inflammatory response at the maternal-fetal interface. We used a well-established model to study infection and infection-associated inflammation during preterm birth in the mouse. We have shown that IL22 is upregulated to respond to an intrauterine lipopolysaccharide administration and plays an important role in controlling the risk of inflammation-induced preterm birth. This paper proposes IL22 as a treatment method to combat infection and prevent preterm birth in susceptible patients.

Tumor acidity is the key metabolic feature promoting cancer progression by eliciting immune‐suppression. V‐ATPases on a cancer cell's surface pump out excess protons and acidify the tumor microenvironment (TME). In vivo treatment of ovarian tumors using a monoclonal antibody (a2v‐mAb) directed against V‐ATPase‐V0a2 delays tumor growth by enhancing antitumor immune responses, making it an effective treatment strategy in ovarian cancer.

Interleukin (IL)-22 is recognized as a tumor-supporting cytokine and is implicated in the proliferation of multiple epithelial cancers. In breast cancer, the current knowledge of IL-22 function is based on cell line models and little is known about how IL-22 affects the tumor initiation, proliferation, invasion, and metastasis in the in vivo system. Here, we investigated the tumor stage-specific function of IL-22 in disease development by evaluating the stage-by-stage progression of breast cancer in an IL-22 knockout spontaneous breast cancer mouse model. We found that among all the stages, IL-22 is specifically upregulated in tumor microenvironment (TME) during the malignant transformation stage of breast tumor progression. The deletion of IL-22 gene leads to the arrest of malignant transition stage, and reduced invasion and tumor burden. Administration of recombinant IL-22 in the TME does not influence in vivo tumor initiation and proliferation but only promotes malignant transformation of cancer cells. Mechanistically, deletion of IL-22 gene causes downregulation of epithelial-tomesenchymal transition (EMT)-associated transcription factors in breast tumors, suggesting EMT as the mechanism of regulation of malignancy by IL-22. Clinically, in human breast tumor tissues, increased number of IL-22 + cells in the TME is associated with an aggressive phenotype of breast cancer. For the first time, this study provides an insight into the tumor stage-specific function of IL-22 in breast tumorigenesis.

Objective: To study decidualization-associated endometrial factors. Design: Retrospective cohort study to compare endometrial gene expression patterns in women experiencing reproductive failure including recurrent pregnancy loss or unexplained infertility versus fertile controls. Setting: University Reproductive Medicine Center. Patient(s): Women experiencing recurrent reproductive failure including recurrent pregnancy loss or unexplained infertility (n ¼ 42) and fertile controls (n ¼ 18). Intervention(s): Endometrial biopsy samples were analyzed with targeted ribonucleic acid sequencing via next-generation sequencing. Main Outcome Measure(s): The primary end point measurements were the expression of genes important for endometrial transformation during decidualization measured singly and in a combined/cumulative score approach. The secondary end point measurements were receiver operating curve analysis and comparisons between the specific biomarkers. Result(s): The comparison revealed differential expression of factors associated with decidualization, tissue homeostasis, and immune regulation: FOXO1, GZMB, IL15, SCNN1A, SGK1, and SLC2A1. A combined evaluation of these 6 signature factors was designated as a decidualization score in which the maximal score was ''6'' and the minimal was ''0''. Among controls, 89% of the samples had a score R5 and 11% had a score of ''4''. A total of 76% of samples in the patient group had scores %4 and 19% had the lowest score of ''0''. A decidualization score <4 provided evidence of abnormality in the decidualization process with a sensitivity of 76% (95% CI 61%-88%) and specificity of 89% (95% CI 65%-99%). Conclusion(s): Decidualization scoring can determine whether the endometrial molecular profile is implantation-friendly. Further validation of this testing approach is necessary to determine a particular patient population in whom it could be used for selecting patients that require therapeutic actions to improve endometrial conditions prior to the in vitro fertilization procedure (Fertil Steril Rep Ò 2021;2:95-103. Ó2020 by American Society for Reproductive Medicine.

The uterine endometrium uniquely regenerates after menses, postpartum, or after breaks in the uterine layer integrity throughout women’s lives. Direct cell–cell contacts ensured by tight and adherens junctions play an important role in endometrial integrity. Any changes in these junctions can alter the endometrial permeability of the uterus and have an impact on the regeneration of uterine layers. Interleukin 22 (IL-22) is a cytokine that is recognized for its role in epithelial regeneration. Moreover, it is crucial in controlling the inflammatory response in mucosal tissues. Here, we studied the role of IL-22 in endometrial recovery after inflammation-triggered abortion. Fecundity of mice was studied in consecutive matings of the same animals after lipopolysaccharide (LPS) (10 µg per mouse)-triggered abortion. The fecundity rate after the second mating was substantially different between IL-22 knockout (IL-22−/−) (9.1%) and wild-type (WT) (71.4%) mice (p &lt; 0.05), while there was no difference between the groups in the initial mating, suggesting that IL-22 deficiency might be associated with secondary infertility. A considerable difference was observed between IL-22−/− and WT mice in the uterine clearance following LPS-triggered abortion. Gross examination of the uteri of IL-22−/− mice revealed non-viable fetuses retained inside the horns (delayed clearance). In contrast, all WT mice had completed abortion with total clearance after LPS exposure. We also discovered that IL-22 deficiency is associated with a decreased expression of tight junctions (claudin-2 and claudin-10) and cell surface pathogen protectors (mucin-1). Moreover, IL-22 has a role in the remodeling of the uterine tissue in the inflammatory environment by regulating epithelial–mesenchymal transition markers called E- and N-cadherin. Therefore, IL-22 contributes to the proper regeneration of endometrial layers after inflammation-triggered abortion. Thus, it might have a practical significance to be utilized as a treatment option postpartum (enhanced regeneration function) and in secondary infertility caused by inflammation (enhanced barrier/protector function).

IL-22 is important for proliferation and progression of various epithelial cancers. However, in breast cancer, the current knowledge of IL-22 function is based on cell line models and lacks information on stage-specific involvement of IL-22 in multistage pathogenesis of disease. Here, we investigated whether IL-22 expression in the tumor microenvironment (TME) is a stage-specific requirement and if its inhibition can affect that specific stage of cancer progression. We show that the absence of IL-22 in TME did not hinder the initiation and proliferation of cancer but inhibited the invasion and metastasis of cancer. The influence of IL-22 on hyperplasia, adenoma, early carcinoma and late carcinoma stages of cancer was investigated using IL-22-/-/MMTV-PyMT spontaneous breast cancer mouse model. IL-22 levels were evaluated at these stages of cancer progression and validated in stage-specific specimens of human breast cancer. A variety of histopathological, in vivo and in vitroproliferation, migration, invasion and gene expression assays were performed on tumor tissues and purified epithelial cells. Results showed that IL-22 was absent in TME during initiation and hyperplasia stages of breast cancer. It was expressed during early carcinoma and significantly increased as tumor progressed to malignant stage. In human samples, IL-22 was poorly expressed in high and low grade ductal carcinoma in situ. However, it was significantly higher in invasive or metastatic carcinoma compared to ductal carcinoma in situ. Histological examinations revealed an inhibition in the malignant transformation of epithelial cells during invasion stage in IL-22-/- tumors. No difference was observed in initiation and hyperplasia stages of cancer between IL-22-/- and control mice. Ex vivo treatment of IL-22 increased the migration and invasion, but not the proliferation, of purified epithelial cancer cells. RNAseq analysis of premalignant stage epithelial cells revealed down regulation in genes associated with EMT (Epithelial to Mesenchymal Transition) pathway in IL-22-/- mice. These results show that, in breast cancer, IL-22 is not essential for cell proliferation but it is necessary for malignant transformation of cancer cells which is the critical stage for metastasis. Inhibition of IL-22 can hinder cancer cell malignancy and therefore, it can be an effective therapeutic target to control breast cancer metastasis. Citation Format: Gajendra K. Katara, Arpita Kulshrestha, Sylvia Schneiderman, Safaa Ibrahim, Mahmood Bilal, Valerie E. Riehl, Kenneth D. Beaman. IL-22 is specifically required for malignancy in breast cancer: A potential target to control cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4600.

No abstract

The high mortality rate in ovarian cancer (OVCA) is currently the most pressing concern despite the research advancements. It is still not clear how to effectively treat OVCA patients to prevent a relapse or to treat the relapse tumors that display a drug-resistant profile. To address this issue, this study targets a uniquely expressed pH regulator in the tumor microenvironment as a strategy to treat ovarian cancer. In order to survive the metabolic acidosis, cancer cells overexpress pH regulators on their surface to pump out excess protons/lactic acid. This, in turn, acidifies the tumor microenvironment and promotes tumor invasion/chemoresistance. The a2-Vacuolar-ATPases (V-ATPases) are the major pH-sensing unit of the V-ATPase proton pumps and are abundantly expressed on the surface of ovarian cancer cells. To establish the clinical importance, our findings show that a2-V-ATPases are overexpressed in all morphologic subtypes and stages of human OVCA and are absent on normal ovarian tissues. We further examined the therapeutic potential of monoclonal antibody against a2-V-ATPase (V0a2-mab) in controlling tumor growth in the preclinical mouse model. In vivo V0a2-mab treatment (300μg in PBS; i.p) resulted in a significantly delayed tumor growth compared to control, with no apparent in vivo toxicity in athymic nude mice xenograft model. The delayed tumor growth was attributed to high immune infiltration with increased leukocyte population and an enhanced iNOS expression compared to control mice. These results show that V-ATPases are overexpressed in the tumor microenvironment and their inhibition impairs OVCA growth by interfering with tumor acidification that enhances the antitumor responses. In conclusion, the study demonstrates that targeting V-ATPase pH regulators is an effective treatment strategy in ovarian cancer. Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Sylvia Schneiderman, Valerie E. Riehl, Alexandria N. Young, Shayna Levine, Safaa Ibrahim, Mahmood Bilal, Alice Gilman-Sachs, Kenneth D. Beaman. Targeting the pH regulators in the tumor microenvironment for ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B64.