RESUMEN
Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. The major clinical challenge includes the asymptomatic state of the disease, making diagnosis possible only at advanced stages. Another OC complication is the high relapse rate and poor prognosis following the standard first-line treatment with platinum-based chemotherapy. At present, numerous clinical trials are being conducted focusing on immunotherapy in OC; nevertheless, there are still no FDA-approved indications. Personalized decision regarding the immunotherapy, including immune checkpoint blockade and immune cell-based immunotherapies, can depend on the effective antigen presentation required for the cytotoxic immune response. The major aim of our study was to uncover tumor-specific transcriptional and epigenetic changes in peripheral blood monocytes in patients with high-grade serous ovarian cancer (HGSOC). Another key point was to elucidate how chemotherapy can reprogram monocytes and how that relates to changes in other immune subpopulations in the blood. To this end, we performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from patients with HGSOC who underwent neoadjuvant chemotherapeutic treatment (NACT) and in treatment-naïve patients. Monocyte cluster was significantly affected by tumor-derived factors as well as by chemotherapeutic treatment. Bioinformatical analysis revealed three distinct monocyte subpopulations within PBMCs based on feature gene expression - CD14.Mn.S100A8.9hi, CD14.Mn.MHC2hi and CD16.Mn subsets. The intriguing result was that NACT induced antigen presentation in monocytes by the transcriptional upregulation of MHC class II molecules, but not by epigenetic changes. Increased MHC class II gene expression was a feature observed across all three monocyte subpopulations after chemotherapy. Our data also demonstrated that chemotherapy inhibited interferon-dependent signaling pathways, but activated some TGFb-related genes. Our results can enable personalized decision regarding the necessity to systemically re-educate immune cells to prime ovarian cancer to respond to anti-cancer therapy or to improve personalized prescription of existing immunotherapy in either combination with chemotherapy or a monotherapy regimen.
Asunto(s)
Presentación de Antígeno , Cistadenocarcinoma Seroso , Monocitos , Neoplasias Ováricas , Humanos , Femenino , Monocitos/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Presentación de Antígeno/efectos de los fármacos , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/inmunología , Persona de Mediana Edad , Clasificación del Tumor , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Neoadyuvante/métodos , Epigénesis GenéticaRESUMEN
Nowadays, prostate cancer is one of the most common forms of malignant neoplasms in men all over the world. Against the background of increasing incidence, there is a high mortality rate from prostate cancer, which is associated with an inadequate treatment strategy. Such a high prevalence of prostate cancer requires the development of methods that can ensure early detection of the disease, improve the effectiveness of treatment, and predict the therapeutic effect. Under these circumstances, it becomes crucial to focus on the development of effective diagnostic and therapeutic approaches. Due to the development of molecular genetic methods, a large number of studies have been accumulated on the role of epigenetic regulation of gene activity in cancer development, since it is epigenetic changes that can be detected at the earliest stages of cancer development. The presence of epigenetic aberrations in tumor tissue and correlations with drug resistance suggest new therapeutic approaches. Detection of epigenetic alterations such as CpG island methylation, histone modification, and microRNAs as biomarkers will improve the diagnosis of the disease, and the use of these strategies as targets for therapy will allow for greater personalization of prostate cancer treatment.
Asunto(s)
Metilación de ADN , Epigénesis Genética , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/terapia , Epigénesis Genética/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Islas de CpG/genéticaRESUMEN
Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocyte-derived and TAM-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer.
Asunto(s)
Neoplasias de la Próstata , Calidad de Vida , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Biomarcadores , Antígeno Prostático Específico , Epigénesis GenéticaRESUMEN
Bladder cancer (BLCA) is one of the most common types of malignant tumors of the urogenital system in adults. Globally, the incidence of BLCA is more than 500,000 new cases worldwide annually, and every year, the number of registered cases of BLCA increases noticeably. Currently, the diagnosis of BLCA is based on cystoscopy and cytological examination of urine and additional laboratory and instrumental studies. However, cystoscopy is an invasive study, and voided urine cytology has a low level of sensitivity, so there is a clear need to develop more reliable markers and test systems for detecting the disease with high sensitivity and specificity. Human body fluids (urine, serum, and plasma) are known to contain significant amounts of tumorigenic nucleic acids, circulating immune cells and proinflammatory mediators that can serve as noninvasive biomarkers, particularly useful for early cancer detection, follow-up of patients, and personalization of their treatment. The review describes the most significant advances in epigenetics of BLCA.