RESUMO
Triple-negative breast cancer (TNBC) afflicts women at a younger age than other breast cancers and is associated with a worse clinical outcome. This poor clinical outcome is attributed to a lack of defined targets and patient-to-patient heterogeneity in target antigens and immune responses. To address such heterogeneity, we tested the efficacy of a personalized vaccination approach for the treatment of TNBC using the 4T1 murine TNBC model. We isolated tumor membrane vesicles (TMVs) from homogenized 4T1 tumor tissue and incorporated glycosyl phosphatidylinositol (GPI)-anchored forms of the immunostimulatory B7-1 (CD80) and IL-12 molecules onto these TMVs to make a TMV vaccine. Tumor-bearing mice were then administered with the TMV vaccine either alone or in combination with immune checkpoint inhibitors. We show that TMV-based vaccine immunotherapy in combination with anti-CTLA-4 mAb treatment upregulated immunomodulatory cytokines in the plasma, significantly improved survival, and reduced pulmonary metastasis in mice compared to either therapy alone. The depletion of CD8+ T cells, but not CD4+ T cells, resulted in the loss of efficacy. This suggests that the vaccine acts via tumor-specific CD8+ T cell immunity. These results suggest TMV vaccine immunotherapy as a potential enhancer of immune checkpoint inhibitor therapies for metastatic triple-negative breast cancer.
Assuntos
Vacinas Anticâncer , Neoplasias de Mama Triplo Negativas , Animais , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4 , Linhagem Celular Tumoral , Humanos , Imunoterapia , Interleucina-12 , Camundongos , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
Carcinoma-associated fibroblasts (CAFs) are abundant stromal cells in tumor microenvironment that are critically involved in cancer progression. Contrasting reports have shown that CAFs can have either pro- or antitumorigenic roles, indicating that CAFs are functionally heterogeneous. Therefore, to precisely target the cancer-promoting CAF subsets, it is necessary to identify specific markers to define these subpopulations and understand their functions. We characterized two CAFs subsets from 28 non-small cell lung cancer (NSCLC) patient tumors that were scored and classified based on desmoplasia [mainly characterized by proliferating CAFs; high desmoplastic CAFs (HD-CAF; nâ¯=â¯15) and low desmoplastic CAFs (LD-CAF; nâ¯=â¯13)], which is an independent prognostic factor. Here, for the first time, we demonstrate that HD-CAFs and LD-CAFs show different tumor-promoting abilities. HD-CAFs showed higher rate of collagen matrix remodeling, invasion, and tumor growth compared to LD-CAFs. Transcriptomic analysis identified 13 genes that were differentially significant (fold ≥1.5; adjusted P value < .1) between HD-CAFs and LD-CAFs. The top upregulated differentially expressed gene, ST8SIA2 (11.3 fold; adjusted P valueâ¯=â¯.02), enhanced NSCLC tumor cell invasion in 3D culture compared to control when it was overexpressed in CAFs, suggesting an important role of ST8SIA2 in cancer cell invasion. We confirmed the protumorigenic role of ST8SIA2, showing that ST8SIA2 was significantly associated with the risk of relapse in three independent NSCLC clinical datasets. In summary, our studies show that functional heterogeneity in CAF plays key role in promoting cancer cell invasion in NSCLC.
Assuntos
Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/patologia , Sialiltransferases/metabolismo , Animais , Biomarcadores Tumorais/genética , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular , Proliferação de Células , Estudos de Coortes , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos SCID , Invasividade Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Sialiltransferases/genética , Células Estromais/metabolismo , Células Estromais/patologia , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Previous studies on the influence of alcohol intake and smoking on bone mineral density (BMD) in men are inconsistent and the effect of these variables on BMD in physically active men is yet to be explored. OBJECTIVE: To investigate the influence of alcohol intake and smoking on BMD in a cohort of males with well-defined lifestyle conditions. DESIGN: Men from the armed forces (n=400) having uniform and defined routines were enrolled. BMD was measured by DXA and participants were grouped according to lifestyle variables. Hormonal parameters were measured by immunoassays. RESULTS: Participants with intake of >24 g/wk of alcohol had significantly higher BMD at femur compared to non-alcohol consumers (p=0.0001) and a linear increase in mean femoral BMD over increasing categories of alcohol intake (p(trend)<0.0001) was observed. Smoking was negatively associated with femoral BMD. In multiple regression analysis, age, BMI, alcohol consumption and smoking were independent predictors of femoral BMD, explaining 10.6% variance. At lumbar spine, age, height and BMI were independent predictors, explaining 9.4% variance in BMD. The concentrations of total testosterone, free testosterone, bioavailable testosterone and PTH were low (p<0.0001) whereas estradiol (p=0.02), free and bioavailable estradiol (p<0.001) were high in alcohol consumers compared to non-consumers. In multiple regression analysis alcohol intake and height explained 5.5% variance in estradiol(.) CONCLUSIONS: In physically active men with well-defined lifestyle conditions, alcohol consumption was associated with higher femoral BMD, the effect of alcohol is complex and is probably partly mediated by influencing the sex steroid levels.
