Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4 + and CD8 + T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule – ARG1, mitigating anti-tumor immune responses.

Antenatal care of women with mental disorders requires close cooperation between the obstetricians and psychiatrists specialised in the mental disorders due to somatic state. Such cooperation should lead to preventing both obstetric and psychiatric complications during the pregnancy and labour in women experiencing symptoms of mental disorders.

Objective: Pelvic organ prolapse (POP) is a common morbidity that affects many women and significantly decreases quality of life. The severity and the impact of the prolapse on the quality of life are important parameters in the management and follow-up of affected patients. The aim of this validation study was to validate the Polish version of the Prolapse Quality of Life questionnaire (P-QoL). Material and methods:The P-QOL questionnaire was translated into Polish and administered to women recruited from two gynecological outpatient clinics (n = 231). Both symptomatic and asymptomatic women were included in the study and examined in supine position using the Pelvic Organ Prolapse Quantification System (POP-Q). The validity was assessed by comparing symptom scores and quality-of-life scores between symptomatic and asymptomatic women.Results: A total number of 154 symptomatic and 77 asymptomatic women were included. There was a strong correlation between severity of the disease based on physical findings (POP-Q scale) and the P-QoL scores in main prolapse quality-of-life domains. The overall scores for each life domain were significantly different between symptomatic and asymptomatic women (p < 0.001). All the questions regarding symptoms showed significant differences (p < 0.001) between both groups. Conclusions:The Polish version of P-QoL is a valid, reliable, and easily comprehensible instrument to assess quality of life and symptoms in Polish-speaking women suffering from urogenital prolapse.

CelDotychczas opisano kilka przypadków psychoz indukowanych stosowaniem cytrynianu klomifenu, używanego w celu stymulacji owulacji. Jednak dane dotyczące rozpowszechnienia objawów psychotycznych wśród kobiet leczonych z powodu niepłodności są niejednoznaczne. Nadal niewiele wiadomo na temat ewentualnych psychiatrycznych powikłań preparatów farmakologicznych stosowanych w technikach rozrodu wspomaganego. Prezentujemy przypadek pacjentki, u której w przebiegu drugiej z kolei procedury zapłodnienia pozaustrojowego rozwinęły się przemijające objawy psychotyczne. Wnioski płynące z przeglądu piśmiennictwa (przeprowadzonego w oparciu o zasoby bazy danych Medline) sugerują, że dotychczas nie opisywano przypadków występowania psychozy »okołostymulacyjnej« w przebiegu procedur zapłodnienia pozaustrojowego z zastosowaniem cytrynianu klomifenu i bromokryptyny. Autorzy niniejszej pracy nie ograniczyli się do omówienia tego rzadkiego zjawiska klinicznego, ale również pokusili się o podsumowanie obecnego stanu wiedzy na temat zależności pomiędzy strategiami farmakoterapeutycznymi stosowanymi w ramach procedur zapłodnienia pozaustrojowego, a ryzykiem rozwoju zaburzeń psychotycznych.MetodaOpis przypadkuWyniki-WnioskiPrawdopodobnym mechanizmem wyzwalającym objawy psychotyczne w opisywanym przypadku było zastosowanie w celu indukcji owulacji-cytrynianu klomifenu w skojarzeniu z bromokryptyną stosowaną w przebiegu przewlekłej hiperprolaktynemii . Terapia skojarzona cytrynianem klomifenu oraz bromokryptyną może stanowić farmakologiczny model hiperdopaminergii wraz z indukowaniem niefizjologicznych wahań poziomu estrogenów w osoczu. Powyższy schemat leczenia może warunkować zwiększenie podatności do rozwoju objawów psychotycznych. Zaś wpływ takiej terapii należy rozważyć w razie wystąpienia ewentualnych powikłań psychotycznych u pacjentek poddawanych technikom rozrodu wspomaganego.

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Aim/Background: Depletion of essential (L-tryptophan) or semi-essential (L-arginine) amino acids has been shown to suppress antitumor immune responses. Arginase-1 (Arg-1) is a cytosolic enzyme catalyzing degradation of L-arginine to L-ornithine and urea. Several studies have shown the presence of abundant Arg-1 in either tumor cells or in tumor-infiltrating myeloid cells of neutrophilic or monocytic origin. This in turn, leads to downregulation of CD3-zeta levels in T cells and correlates with suppressed antitumor immunity. In patients with ovarian cancer (OvCa), exosomes released by tumor cells (TEX) are detected in body fluids including plasma or ascites and carry proteins that are expressed by OvCa cells. Here we report that OvCa cells release Arg-1 in TEX and investigate the influence of OvCa TEX-derived Arg-1 on the antitumor effector mechanisms of immune response. Methods: TEX were isolated by ultracentrifugation or exclusion chromatography and verified by Western blotting, NanoSight and electron microscopy. The presence of Arg-1 in TEX was determined by Western blotting and the Arg-1 activity was assessed using an enzymatic assay that measured conversion of arginine into urea. Immunohistochemical Arg-1 expression data in primary OvCa lesions were correlated to clinico-pathological characteristics. Effects of TEX Arg-1 on immune cells were analyzed by in vitro proliferation assay and flow cytometry. Results: OvCa ascites contained higher levels of exosomal Arg-1 as compared with the fluids obtained from benign ovarian cysts. Enzymatically active Arg-1 was detected in TEX derived from patients’ ascites as well as from ovarian cancer cell lines. High Arg-1 expression in correlated negatively with intratumoral T-cell infiltrates and CD3-zeta expression and was associated with shorter time to recurrence (TTR). In vitro, OvCa-derived Arg-1-positive TEX inhibited CD8+ and CD4+ T-cell proliferation and decreased T-cell receptor expression. We also observed that co-culture of bone-marrow-derived dendritic cells (DC) with TEX isolated from OvCa cells results in the transfer of functionally active Arg-1 that inhibits DCs-primed proliferation of OVA-antigen specific OT-I T cells. We have used TEX isolated from OvCa cells transfected with V5-tagged Arg-1 for these experiments to ensure that this is OvCa-derived, but not endogenous DC-derived arginase that suppresses T cell proliferation. All these in vitro effects were reversed by a novel Arg-1 inhibitor (OAT-1746). Conclusions: Our findings provide the first evidence for the role of Arg-1 in the formation of an immunosuppressive microenvironment in OvCa. We identify a novel mechanism of exosomal Arg-1 distribution from the tumor cells to antigen presenting cells. Inhibition of Arg-1 activity may be an attractive novel anti-cancer strategy. Funding:  NCN - OPUS 6 Program 2013/11/B/NZ6/02790, NCBIR – STRATEGMED2/265503/3/NCBIR/15 Citation Format: Malgorzata Czystowska, Marta Szajnik, Kavita Ramji, Slawomir Gruca, Artur Stefanowicz, Jakub Golab, Dominika Nowis. Ovarian cancer cells release arginase-1-containing exosomes to suppress antitumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3975. doi:10.1158/1538-7445.AM2017-3975