M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer
Journal for ImmunoTherapy of Cancer
BackgroundThe immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has ... more BackgroundThe immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.MethodsRNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC s...
Background: Adjuvanticity, which is the ability of neoplastic cells to deliver danger signals, is... more Background: Adjuvanticity, which is the ability of neoplastic cells to deliver danger signals, is critical for the host immune system to mount spontaneous and therapy-driven anticancer immune responses. One of such signals, i.e., the exposure of calreticulin (CALR) on the membrane of malignant cells experiencing endoplasmic reticulum (ER) stress, is well known for its role in the activation of immune responses to dying cancer cells. However, the potential impact of CALR on the immune contexture of primary and metastatic high-grade serous carcinomas (HGSCs) and its prognostic value for patients with HGSC remains unclear. Method: We harnessed a retrospective cohort of primary (no = 152) and metastatic (no = 74) tumor samples from HGSC patients to investigate the CALR expression in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 302 HGSC samples was used as a confirmatory approach. Results: We demonstrate that CALR exposure on the surface of primary and metastatic HGSC cells is driven by a chemotherapy-independent ER stress response and culminates with the establishment of a local immune contexture characterized by T H 1 polarization and cytotoxic activity that enables superior clinical benefits. Conclusions: Our data indicate that CALR levels in primary and metastatic HGSC samples have robust prognostic value linked to the activation of clinically-relevant innate and adaptive anticancer immune responses.
A high density of tumor-infiltrating CD8 + T cells and CD20 + B cells correlates with prolonged s... more A high density of tumor-infiltrating CD8 + T cells and CD20 + B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP + DCs is robustly associated with an immune contexture characterized by T H 1 polarization and cytotoxic activity. We showed that both mature DCs and CD20 + B cells play a critical role in the generation of a clinically-favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP + DCs and CD20 + B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naïve HGSC patients. Our findings suggest that the presence of mature, DC-LAMP + DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically-relevant anticancer immunity.
In order to select a suitable combination of cancer cell lines as an appropriate source of antige... more In order to select a suitable combination of cancer cell lines as an appropriate source of antigens for dendritic cell-based immunotherapy of ovarian cancer, we analyzed the expression level of 21 tumor associated antigens (BIRC5, CA125, CEA, DDX43, EPCAM, FOLR1, Her-2/neu, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MUC-1, NY-ESO-1, PRAME, p53, TPBG, TRT, WT1) in 4 established ovarian cancer cell lines and in primary tumor cells isolated from the high-grade serous epithelial ovarian cancer tissue. More than 90% of tumor samples expressed very high levels of CA125, FOLR1, EPCAM and MUC-1 and elevated levels of Her-2/neu, similarly to OVCAR-3 cell line. The combination of OV-90 and OVCAR-3 cell lines showed the highest overlap with patients' samples in the TAA expression profile.
Superoxide dismutase mimetic tempol inhibits hypoxic pulmonary vasoconstriction in rats independently on either nitric oxide production or basal tone of pulmonary vessels
[Active cellular immunotherapy of ovarian cancer using dendritic cells]
Ceská gynekologie / Ceská lékarská spolecnost J. Ev. Purkyne, 2012
Overview and comparison of current results of studies dealing with the development and applicatio... more Overview and comparison of current results of studies dealing with the development and application of anti-cancer vaccines based on dendritic cells in ovarian cancer. Review. Department of Obstetrics and Gynaecology Charles University, Prague, 2nd Faculty of Medicine and University Hospital Motol, Department of Immunology 2nd Faculty of Medicine and University Hospital Motol. Ovarian carcinoma (OVCA) is highly sensitive to chemotherapy; however despite this results from treatment are fairly unsatisfactory. Bearing this in mind, it is important to look for new ways to better understand the immunological mechanisms which could affect reactivation of the disease. It is likely that new knowledge in the field of the immunology of ovarian carcinoma could improve monitoring of the disease and help to ameliorate prognosis of the disease. One strategy in development is creation of anti-OVCA vaccines. Theese vaccines are made by the fusion of dendritic cell (DC) and tumor cells or its parts (...
[The effectiveness of recurrent stress urinary incontinence treatment after Burch colposuspension failure with transobturatory tape procedure]
Ceská gynekologie / Ceská lékarská spolecnost J. Ev. Purkyne, 2011
To evaluate the safety and efficacy of the transobturatory tape (TOT) procedure in the treatment ... more To evaluate the safety and efficacy of the transobturatory tape (TOT) procedure in the treatment of female recurrent stress urinary incontinence after the Burch colposuspension failure. Retrospective clinical trial. Obstetrics and Gynecology Department, Charles University, 2nd Medical School and Faculty Hospital Motol, Prague. The group of fifteen women was treated for recurrent stress urinary incontinence with TOT procedure. Preoperative evaluation consisted of complete urogynecological examination. The cure rate and complications were determined in postoperative follow up 6 weeks and 12 months after the surgery. The mean age was 58.7 (46-64) years. Burch colposuspension was performed 6.4 (1-13) years before current TOT procedure. The cure rate in 12 month follow-up was 86.6% (13 of 15 patients), one patient was improved (6.7%). Postoperative complications occurred in 2 (13.4%) cases--one lower urinary tract infection and one overactive bladder symptomatology cured by anticholinerg...
Ceská gynekologie / Ceská lékarská spolecnost J. Ev. Purkyne, 2010
Analysis of two cases uterine rupture following caesarian section. Two case studies. Gynecologica... more Analysis of two cases uterine rupture following caesarian section. Two case studies. Gynecological obstetrics clinic, First Medical Faculty and Faculty Hospital Bulovka, Prague. The authors in their article describe two cases of rupture of the uterus in pregnancy prior to delivery. In both cases there was a history of cervicocorporal caesarian section. In the first case the patient was admitted from her home with bleeding, and signed a nonconsent form. The second case concerned a hospitalized patient, in which the first signs of uterine rupture were indicated by fetal heart rate. Both women underwent hysterectomy, paradoxically, in the first case the child was saved and discharged home in good health.
Clinical relevance of regulatory T cells monitoring in the peripheral blood of ovarian cancer patients
Human Immunology, 2014
Tregs play a suppressive role in the control of antitumour immunity. In this study we evaluated t... more Tregs play a suppressive role in the control of antitumour immunity. In this study we evaluated the relevance of prospective monitoring of peripheral blood regulatory T cells (Tregs) as a potential prognostic marker of future outcome of epithelial ovarian cancer in patients with or without a metronomic chemotherapy. 46 patients diagnosed with the ovarian cancer were enrolled in the study and divided into groups according to the stage of the disease, outcome of the surgery and treatment received. Proportions of Tregs in the peripheral blood samples were evaluated using flow cytometry. We show that the early stage of the disease and absence of the tumor residuum after radical surgery are the most important factors predicting a favourable clinical outcome in the ovarian cancer. We did not show any significant effect of consolidation chemotherapy with metronomic doses of etoposide or cyclophosphamide on the peripheral blood Tregs and on the clinical outcome. The slope of the Tregs trend line was a significant predictor of an early relapse, even after controlling for stage and tumor residuum after the surgical debulking by using the Cox proportional hazard model. This study shows that the faster kinetics of Tregs increase in the peripheral blood, expressed as the slope of the Tregs trend line, is a significant predictor of ovarian cancer early relapse hazard. However, due to its relatively low specificity, the informative value of regular monitoring of Tregs kinetics in the peripheral blood for the subsequent clinical outcome is limited.
The type of immune cells that are present within the tumor microenvironment can play a crucial ro... more The type of immune cells that are present within the tumor microenvironment can play a crucial role in the survival of patients. However, little is known about the dynamics of the tumor-infiltrating immune cells during disease progression. We studied the immune cells that infiltrated the tumor tissues of ovarian cancer patients at different stages of disease. The early stages of development of ovarian carcinomas were characterized by a strong Th17 immune response, whereas in stage II patients, recruitment of high numbers of Th1 cells was observed. In disseminated tumors (Stages III-IV), we detected a dominant population of Helios 1 activated regulatory T cells (Tregs) along with high numbers of monocytes/macrophages and myeloid dendritic cells (mDCs). Tumor-infiltrating Tregs had markedly lower expression of CCR4 than circulating Tregs, and the numbers of tumor-infiltrating Tregs significantly correlated with the levels of CCL22 in ovarian tumor cell culture supernatants, suggesting their recruitment via a CCR4/CCL22 interaction. CCL22 was mainly produced by tumor cells, monocytes/ macrophages and mDCs in the primary ovarian tumors, and its expression markedly increased in response to IFNc. Taken together, the specific recruitment of Tregs, probably triggered by inflammatory stimuli, leads to a significant immune suppression in the advanced stages of ovarian cancer.
Immunogenic cell death is characterized by the early surface exposure of chaperones including cal... more Immunogenic cell death is characterized by the early surface exposure of chaperones including calreticulin and HSPs, which affect dendritic cell (DC) maturation and the uptake and presentation of tumor antigens. It has also been shown that it is characterized by the late release of high mobility group box 1 (HMGB1), which acts through Toll-like receptor 4 (TLR4) and augments the presentation of antigens from dying tumor cells to DCs. Most of the data on immunogenic tumor cell death were obtained using mouse models. In this study, we investigated the capacity of clinically used chemotherapeutics to induce immunogenic cell death in human tumor cell lines and primary tumor cells. We found that only anthracyclines induced a rapid translocation of calreticulin, HSP70, and HSP90 to the cell surface and the release of HMGB1 12 hours after the treatment. The interaction of immature DCs with immunogenic tumor cells led to an increased tumor cell uptake and induces moderate phenotypic maturation of DCs. Killed tumor cell-loaded DCs efficiently stimulated tumor-specific IFN-g-producing T cells. DCs pulsed with killed immunogenic tumor cells also induced significantly lower numbers of regulatory T cells than those pulsed with nonimmunogenic tumor cells. These data indicate that human prostate cancer, ovarian cancer, and acute lymphoblastic leukemia cells share the key features of immunogenic cell death with mice tumor cells. These data also identify anthracyclines as anticancer drugs capable of inducing immunogenic cell death in sensitive human tumor cells. Cancer Res; 71(14); 4821-33. Ó2011 AACR.
Ovarian cancer is diagnosed in more than 190,000 new patients every year and is known to have the... more Ovarian cancer is diagnosed in more than 190,000 new patients every year and is known to have the highest mortality rate among gynaecologic cancers. Due to the lack of satisfactory biomarkers and the fact that the disease develops and spreads very rapidly, almost 70% of patients with diagnosed ovarian cancer already suffer from advanced disseminated disease. Since cells that underwent malignant transformation can express antigens recognized by the immune system as foreign, cancer development as well as treatment of the disease is markedly affected by the patient's immune system. To extend the knowledge of tumor-associated antigens (TAA) expressed by primary ovarian cancer cells, we analysed expression of Her-2/ neu, CA-125, FBP, NY-ESO-1, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A10 and MAGE-A12 TAA genes using quantitative RT-PCR. Three most frequent TAA genes, Her-2/neu, CA-125 and FBP, were overexpressed in 94%-100% of samples, whereas the expression frequency of the other tested TAA varied between 29% and 59%. Our data show that primary ovarian cancer cells express a wide spectrum of TAA genes which may represent potential targets of immunotherapy and/or might be revealed as possible prognostic factors in ovarian cancer patients. The project was supported by project MSM 0021620812 from the Czech Ministry of Education and grant GACR 310/08/0838.
M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer
Journal for ImmunoTherapy of Cancer
BackgroundThe immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has ... more BackgroundThe immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.MethodsRNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC s...
Background: Adjuvanticity, which is the ability of neoplastic cells to deliver danger signals, is... more Background: Adjuvanticity, which is the ability of neoplastic cells to deliver danger signals, is critical for the host immune system to mount spontaneous and therapy-driven anticancer immune responses. One of such signals, i.e., the exposure of calreticulin (CALR) on the membrane of malignant cells experiencing endoplasmic reticulum (ER) stress, is well known for its role in the activation of immune responses to dying cancer cells. However, the potential impact of CALR on the immune contexture of primary and metastatic high-grade serous carcinomas (HGSCs) and its prognostic value for patients with HGSC remains unclear. Method: We harnessed a retrospective cohort of primary (no = 152) and metastatic (no = 74) tumor samples from HGSC patients to investigate the CALR expression in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 302 HGSC samples was used as a confirmatory approach. Results: We demonstrate that CALR exposure on the surface of primary and metastatic HGSC cells is driven by a chemotherapy-independent ER stress response and culminates with the establishment of a local immune contexture characterized by T H 1 polarization and cytotoxic activity that enables superior clinical benefits. Conclusions: Our data indicate that CALR levels in primary and metastatic HGSC samples have robust prognostic value linked to the activation of clinically-relevant innate and adaptive anticancer immune responses.
A high density of tumor-infiltrating CD8 + T cells and CD20 + B cells correlates with prolonged s... more A high density of tumor-infiltrating CD8 + T cells and CD20 + B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP + DCs is robustly associated with an immune contexture characterized by T H 1 polarization and cytotoxic activity. We showed that both mature DCs and CD20 + B cells play a critical role in the generation of a clinically-favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP + DCs and CD20 + B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naïve HGSC patients. Our findings suggest that the presence of mature, DC-LAMP + DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically-relevant anticancer immunity.
In order to select a suitable combination of cancer cell lines as an appropriate source of antige... more In order to select a suitable combination of cancer cell lines as an appropriate source of antigens for dendritic cell-based immunotherapy of ovarian cancer, we analyzed the expression level of 21 tumor associated antigens (BIRC5, CA125, CEA, DDX43, EPCAM, FOLR1, Her-2/neu, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MUC-1, NY-ESO-1, PRAME, p53, TPBG, TRT, WT1) in 4 established ovarian cancer cell lines and in primary tumor cells isolated from the high-grade serous epithelial ovarian cancer tissue. More than 90% of tumor samples expressed very high levels of CA125, FOLR1, EPCAM and MUC-1 and elevated levels of Her-2/neu, similarly to OVCAR-3 cell line. The combination of OV-90 and OVCAR-3 cell lines showed the highest overlap with patients' samples in the TAA expression profile.
Superoxide dismutase mimetic tempol inhibits hypoxic pulmonary vasoconstriction in rats independently on either nitric oxide production or basal tone of pulmonary vessels
[Active cellular immunotherapy of ovarian cancer using dendritic cells]
Ceská gynekologie / Ceská lékarská spolecnost J. Ev. Purkyne, 2012
Overview and comparison of current results of studies dealing with the development and applicatio... more Overview and comparison of current results of studies dealing with the development and application of anti-cancer vaccines based on dendritic cells in ovarian cancer. Review. Department of Obstetrics and Gynaecology Charles University, Prague, 2nd Faculty of Medicine and University Hospital Motol, Department of Immunology 2nd Faculty of Medicine and University Hospital Motol. Ovarian carcinoma (OVCA) is highly sensitive to chemotherapy; however despite this results from treatment are fairly unsatisfactory. Bearing this in mind, it is important to look for new ways to better understand the immunological mechanisms which could affect reactivation of the disease. It is likely that new knowledge in the field of the immunology of ovarian carcinoma could improve monitoring of the disease and help to ameliorate prognosis of the disease. One strategy in development is creation of anti-OVCA vaccines. Theese vaccines are made by the fusion of dendritic cell (DC) and tumor cells or its parts (...
[The effectiveness of recurrent stress urinary incontinence treatment after Burch colposuspension failure with transobturatory tape procedure]
Ceská gynekologie / Ceská lékarská spolecnost J. Ev. Purkyne, 2011
To evaluate the safety and efficacy of the transobturatory tape (TOT) procedure in the treatment ... more To evaluate the safety and efficacy of the transobturatory tape (TOT) procedure in the treatment of female recurrent stress urinary incontinence after the Burch colposuspension failure. Retrospective clinical trial. Obstetrics and Gynecology Department, Charles University, 2nd Medical School and Faculty Hospital Motol, Prague. The group of fifteen women was treated for recurrent stress urinary incontinence with TOT procedure. Preoperative evaluation consisted of complete urogynecological examination. The cure rate and complications were determined in postoperative follow up 6 weeks and 12 months after the surgery. The mean age was 58.7 (46-64) years. Burch colposuspension was performed 6.4 (1-13) years before current TOT procedure. The cure rate in 12 month follow-up was 86.6% (13 of 15 patients), one patient was improved (6.7%). Postoperative complications occurred in 2 (13.4%) cases--one lower urinary tract infection and one overactive bladder symptomatology cured by anticholinerg...
Ceská gynekologie / Ceská lékarská spolecnost J. Ev. Purkyne, 2010
Analysis of two cases uterine rupture following caesarian section. Two case studies. Gynecologica... more Analysis of two cases uterine rupture following caesarian section. Two case studies. Gynecological obstetrics clinic, First Medical Faculty and Faculty Hospital Bulovka, Prague. The authors in their article describe two cases of rupture of the uterus in pregnancy prior to delivery. In both cases there was a history of cervicocorporal caesarian section. In the first case the patient was admitted from her home with bleeding, and signed a nonconsent form. The second case concerned a hospitalized patient, in which the first signs of uterine rupture were indicated by fetal heart rate. Both women underwent hysterectomy, paradoxically, in the first case the child was saved and discharged home in good health.
Clinical relevance of regulatory T cells monitoring in the peripheral blood of ovarian cancer patients
Human Immunology, 2014
Tregs play a suppressive role in the control of antitumour immunity. In this study we evaluated t... more Tregs play a suppressive role in the control of antitumour immunity. In this study we evaluated the relevance of prospective monitoring of peripheral blood regulatory T cells (Tregs) as a potential prognostic marker of future outcome of epithelial ovarian cancer in patients with or without a metronomic chemotherapy. 46 patients diagnosed with the ovarian cancer were enrolled in the study and divided into groups according to the stage of the disease, outcome of the surgery and treatment received. Proportions of Tregs in the peripheral blood samples were evaluated using flow cytometry. We show that the early stage of the disease and absence of the tumor residuum after radical surgery are the most important factors predicting a favourable clinical outcome in the ovarian cancer. We did not show any significant effect of consolidation chemotherapy with metronomic doses of etoposide or cyclophosphamide on the peripheral blood Tregs and on the clinical outcome. The slope of the Tregs trend line was a significant predictor of an early relapse, even after controlling for stage and tumor residuum after the surgical debulking by using the Cox proportional hazard model. This study shows that the faster kinetics of Tregs increase in the peripheral blood, expressed as the slope of the Tregs trend line, is a significant predictor of ovarian cancer early relapse hazard. However, due to its relatively low specificity, the informative value of regular monitoring of Tregs kinetics in the peripheral blood for the subsequent clinical outcome is limited.
The type of immune cells that are present within the tumor microenvironment can play a crucial ro... more The type of immune cells that are present within the tumor microenvironment can play a crucial role in the survival of patients. However, little is known about the dynamics of the tumor-infiltrating immune cells during disease progression. We studied the immune cells that infiltrated the tumor tissues of ovarian cancer patients at different stages of disease. The early stages of development of ovarian carcinomas were characterized by a strong Th17 immune response, whereas in stage II patients, recruitment of high numbers of Th1 cells was observed. In disseminated tumors (Stages III-IV), we detected a dominant population of Helios 1 activated regulatory T cells (Tregs) along with high numbers of monocytes/macrophages and myeloid dendritic cells (mDCs). Tumor-infiltrating Tregs had markedly lower expression of CCR4 than circulating Tregs, and the numbers of tumor-infiltrating Tregs significantly correlated with the levels of CCL22 in ovarian tumor cell culture supernatants, suggesting their recruitment via a CCR4/CCL22 interaction. CCL22 was mainly produced by tumor cells, monocytes/ macrophages and mDCs in the primary ovarian tumors, and its expression markedly increased in response to IFNc. Taken together, the specific recruitment of Tregs, probably triggered by inflammatory stimuli, leads to a significant immune suppression in the advanced stages of ovarian cancer.
Immunogenic cell death is characterized by the early surface exposure of chaperones including cal... more Immunogenic cell death is characterized by the early surface exposure of chaperones including calreticulin and HSPs, which affect dendritic cell (DC) maturation and the uptake and presentation of tumor antigens. It has also been shown that it is characterized by the late release of high mobility group box 1 (HMGB1), which acts through Toll-like receptor 4 (TLR4) and augments the presentation of antigens from dying tumor cells to DCs. Most of the data on immunogenic tumor cell death were obtained using mouse models. In this study, we investigated the capacity of clinically used chemotherapeutics to induce immunogenic cell death in human tumor cell lines and primary tumor cells. We found that only anthracyclines induced a rapid translocation of calreticulin, HSP70, and HSP90 to the cell surface and the release of HMGB1 12 hours after the treatment. The interaction of immature DCs with immunogenic tumor cells led to an increased tumor cell uptake and induces moderate phenotypic maturation of DCs. Killed tumor cell-loaded DCs efficiently stimulated tumor-specific IFN-g-producing T cells. DCs pulsed with killed immunogenic tumor cells also induced significantly lower numbers of regulatory T cells than those pulsed with nonimmunogenic tumor cells. These data indicate that human prostate cancer, ovarian cancer, and acute lymphoblastic leukemia cells share the key features of immunogenic cell death with mice tumor cells. These data also identify anthracyclines as anticancer drugs capable of inducing immunogenic cell death in sensitive human tumor cells. Cancer Res; 71(14); 4821-33. Ó2011 AACR.
Ovarian cancer is diagnosed in more than 190,000 new patients every year and is known to have the... more Ovarian cancer is diagnosed in more than 190,000 new patients every year and is known to have the highest mortality rate among gynaecologic cancers. Due to the lack of satisfactory biomarkers and the fact that the disease develops and spreads very rapidly, almost 70% of patients with diagnosed ovarian cancer already suffer from advanced disseminated disease. Since cells that underwent malignant transformation can express antigens recognized by the immune system as foreign, cancer development as well as treatment of the disease is markedly affected by the patient's immune system. To extend the knowledge of tumor-associated antigens (TAA) expressed by primary ovarian cancer cells, we analysed expression of Her-2/ neu, CA-125, FBP, NY-ESO-1, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A10 and MAGE-A12 TAA genes using quantitative RT-PCR. Three most frequent TAA genes, Her-2/neu, CA-125 and FBP, were overexpressed in 94%-100% of samples, whereas the expression frequency of the other tested TAA varied between 29% and 59%. Our data show that primary ovarian cancer cells express a wide spectrum of TAA genes which may represent potential targets of immunotherapy and/or might be revealed as possible prognostic factors in ovarian cancer patients. The project was supported by project MSM 0021620812 from the Czech Ministry of Education and grant GACR 310/08/0838.
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