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Cancer vaccines are increasingly being studied as a possible strategy to prevent and treat cancers. While several prophylactic vaccines for virus-caused cancers are approved and efficiently used worldwide, the development of therapeutic cancer vaccines needs to be further implemented. Virus-like particles (VLPs) are self-assembled protein structures that mimic native viruses or bacteriophages but lack the replicative material. VLP platforms are designed to display single or multiple antigens with a high-density pattern, which can trigger both cellular and humoral responses. The aim of this review is to provide a comprehensive overview of preventive VLP-based vaccines currently approved worldwide against HBV and HPV infections or under evaluation to prevent virus-caused cancers. Furthermore, preclinical and early clinical data on prophylactic and therapeutic VLP-based cancer vaccines were summarized with a focus on HER-2-positive breast cancer.
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Bacteriófagos , Vacunas contra el Cáncer , Neoplasias , Viroides , Vacunas contra el Cáncer/uso terapéutico , Núcleo Celular , Inmunoterapia , Neoplasias/terapiaRESUMEN
BACKGROUND: Insulin-like Growth Factor Receptor-1 (IGF1R) system sustains the genesis of rhabdomyosarcoma through IGF2 autocrine overexpression. While several IGF1R-targeted strategies have been investigated to interphere with rhabdomyosarcoma growth, no attempt to neutralize IGF2 has been reported. We therefore studied the possibility to hamper rhabdomyosarcoma growth with passive and active immune approaches targeting IGF2. METHODS: A murine model developing IGF2-overexpressing pelvic rhabdomyosarcoma, along with IGF2-independent salivary carcinoma, was used to investigate the efficacy and specificity of passive anti-IGFs antibody treatment. Active vaccinations with electroporated DNA plasmids encoding murine or human IGF2 were performed to elicit autochthonous anti-IGF2 antibodies. Vaccinated mice received the intravenous injection of rhabdomyosarcoma cells to study the effects of anti-IGF2 antibodies against developing metastases. RESULTS: Passive administration of antibodies neutralizing IGFs delayed the onset of IGF2-overexpressing rhabdomyosarcoma but not of IGF2-independent salivary carcinoma. A DNA vaccine against murine IGF2 did not elicit antibodies, even when combined with Treg-depletion, while a DNA vaccine encoding the human IGF2 gene elicited antibodies crossreacting with murine IGF2. Mice with anti-IGF2 antibodies were partially protected against the metastatic growth of IGF2-addicted rhabdomyosarcoma cells. CONCLUSIONS: Immune targeting of autocrine IGF2 inhibited rhabdomyosarcoma genesis and metastatic growth.
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Comunicación Autocrina , Inmunomodulación , Factor II del Crecimiento Similar a la Insulina/metabolismo , Rabdomiosarcoma/inmunología , Rabdomiosarcoma/metabolismo , Animales , Animales Modificados Genéticamente , Anticuerpos Monoclonales/farmacología , Antineoplásicos Inmunológicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Factor II del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Ratones , Ratas , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/patología , Resultado del TratamientoRESUMEN
Cancer immunoprevention is based on the fact that a functioning immune system controls tumor onset and development in humans and animals, thus leading to the idea that the enhancement of immune responses in healthy individuals could effectively reduce cancer risk later in life. Successful primary immunoprevention of tumors caused by hepatitis B and papilloma viruses is already implemented at the population level with specific vaccines. The immunoprevention of human tumors unrelated to infectious agents is an outstanding challenge. Proof-of-principle preclinical studies in genetically-modified or in carcinogen-exposed mice clearly demonstrated that vaccines and other immunological treatments induce host immune responses that effectively control tumor onset and progression, eventually resulting in cancer prevention. While a straightforward translation to healthy humans is currently unfeasible, a number of pioneering clinical trials showed that cancer immunoprevention can be effectively implemented in human cohorts affected by specific cancer risks, such as preneoplastic/early neoplastic lesions. Future developments will see the implementation of cancer immunoprevention in a wider range of conditions at risk of tumor development, such as the exposure to known carcinogens and genetic predispositions.
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Antineoplásicos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/prevención & control , Lesiones Precancerosas/prevención & control , Animales , Antineoplásicos/inmunología , Vacunas contra el Cáncer/inmunología , Progresión de la Enfermedad , Humanos , Inmunidad/efectos de los fármacos , Inmunidad/inmunología , Ratones , Neoplasias/inmunología , Neoplasias/patología , Lesiones Precancerosas/inmunologíaRESUMEN
INTRODUCTION: We previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine. Since IL-12 can induce the release of interleukin-15 (IL-15), in the present study we investigated the role played by IL-15 in HER2/neu driven mammary carcinogenesis and in its immunoprevention. METHODS: HER2/neu transgenic mice with homozygous knockout of IL-15 (here referred to as IL15KO/NeuT mice) were compared to IL-15 wild-type HER2/neu transgenic mice (NeuT) regarding mammary carcinogenesis, profile of peripheral blood lymphocytes and splenocytes and humoral and cellular responses induced by the vaccine. RESULTS: IL15KO/NeuT mice showed a significantly earlier mammary cancer onset than NeuT mice, with median latency times of 16 and 20 weeks respectively, suggesting a role for IL-15 in cancer immunosurveillance. Natural killer (NK) and CD8+ lymphocytes were significantly lower in IL15KO/NeuT mice compared to mice with wild-type IL-15. The IL-12-adjuvanted allogeneic HER2/neu-expressing cell vaccine was still able to delay mammary cancer onset but efficacy in IL-15-lacking mice vanished earlier: all vaccinated IL15KO/NeuT mice developed tumors within 80 weeks of age (median latency of 53 weeks), whereas more than 70 % of vaccinated NeuT mice remained tumor-free up to 80 weeks of age. Vaccinated IL15KO/NeuT mice showed less necrotic tumors with fewer CD3+ lymphocyes and lacked perforin-positive infiltrating cells compared to NeuT mice. Concerning the anti-vaccine antibody response, antibody titer was unaffected by the lack of IL-15, but less antibodies of IgM and IgG1 isotypes were found in IL15KO/NeuT mice. A lower induction by vaccine of systemic interferon-gamma (IFN-γ) and interleukin-5 (IL-5) was also observed in IL15KO/NeuT mice when compared to NeuT mice. Finally, we found a lower level of CD8+ memory cells in the peripheral blood of vaccinated IL15KO/NeuT mice compared to NeuT mice. CONCLUSIONS: We demonstrated that IL-15 has a role in mammary cancer immunosurveillance and that IL-15-regulated NK and CD8+ memory cells play a role in long-lasting immunoprevention, further supporting the potential use of IL-15 as adjuvant in immunological strategies against tumors.
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Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Interleucina-15/metabolismo , Monitorización Inmunológica , Receptor ErbB-2/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Vacunas contra el Cáncer/inmunología , Quimiotaxis/genética , Quimiotaxis/inmunología , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Interleucina-15/genética , Ratones Noqueados , Ratones Transgénicos , Receptor ErbB-2/genética , Transducción de SeñalRESUMEN
Oncolytic viruses aim to specifically kill tumor cells. A major challenge is the effective targeting of disseminated tumors in vivo. We retargeted herpes simplex virus (HSV) tropism to HER-2 oncoprotein p185, overexpressed in ovary and breast cancers. The HER-2-retargeted R-LM249 exclusively infects and kills tumor cells expressing high levels of human HER-2. Here, we assessed the efficacy of systemically i.p. delivered R-LM249 against disseminated tumors in mouse models that recapitulate tumor spread to the peritoneum in women. The human ovarian carcinoma SK-OV-3 cells implanted intraperitoneally (i.p.) in immunodeficient Rag2â»/â»;Il2rgâ»/â» mice gave rise to a progressive peritoneal carcinomatosis which mimics the fatal condition in advanced human patients. I.p. administration of R-LM249 strongly inhibited carcinomatosis, resulting in 60% of mice free from peritoneal diffusion, and 95% reduction in the total weight of neoplastic nodules. Intraperitoneal metastases are a common outcome in breast cancer: i.p. administration of R-LM249 strongly inhibited the growth of ovarian metastases of HER-2+ MDA-MB-453 breast cells. Brain metastases were also reduced. Cumulatively, upon i.p. administration the HER-2-redirected oncolytic HSV effectively reduced the growth of ovarian and breast carcinoma disseminated to the peritoneal cavity.
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Neoplasias de la Mama/terapia , Herpesvirus Humano 1/genética , Viroterapia Oncolítica/métodos , Virus Oncolíticos/genética , Neoplasias Ováricas/terapia , Neoplasias Peritoneales/terapia , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Supervivencia Celular , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Terapia Genética/métodos , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Herpesvirus Humano 1/fisiología , Humanos , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , Virus Oncolíticos/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/secundario , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Tasa de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: The availability of mice transgenic for the human HER2 gene (huHER2) and prone to the development of HER2-driven mammary carcinogenesis (referred to as FVB-huHER2 mice) prompted us to study active immunopreventive strategies targeting the human HER2 molecule in a tolerant host. METHODS: FVB-huHER2 mice were vaccinated with either IL-12-adjuvanted human HER2-positive cancer cells or DNA vaccine carrying chimeric human-rat HER2 sequences. Onset and number of mammary tumors were recorded to evaluate vaccine potency. Mice sera were collected and passively transferred to xenograft-bearing mice to assess their antitumor efficacy. RESULTS: Both cell and DNA vaccines significantly delayed tumor onset, leading to about 65% tumor-free mice at 70 weeks, whereas mock-vaccinated FVB-huHER2 controls developed mammary tumors at a median age of 45 weeks. In the DNA vaccinated group, 65% of mice were still tumor-free at about 90 weeks of age. The number of mammary tumors per mouse was also significantly reduced in vaccinated mice. Vaccines broke the immunological tolerance to the huHER2 transgene, inducing both humoral and cytokine responses. The DNA vaccine mainly induced a high and sustained level of anti-huHER2 antibodies, the cell vaccine also elicited interferon (IFN)-γ production. Sera of DNA-vaccinated mice transferred to xenograft-carrying mice significantly inhibited the growth of human HER2-positive cancer cells. CONCLUSIONS: Anti-huHER2 antibodies elicited in the tolerant host exert antitumor activity.
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Vacunas contra el Cáncer/inmunología , Neoplasias Mamarias Animales/inmunología , Receptor ErbB-2/inmunología , Vacunas de ADN/inmunología , Traslado Adoptivo , Animales , Anticuerpos/sangre , Formación de Anticuerpos/inmunología , Línea Celular Tumoral , Femenino , Humanos , Interferón gamma/biosíntesis , Interleucina-12/inmunología , Células MCF-7 , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/prevención & control , Ratones , Ratones Transgénicos , Receptor ErbB-2/genética , Bazo/citología , Bazo/trasplanteRESUMEN
BACKGROUND: In non-small cell lung cancer (NSCLC), BRAF class 1 alterations are effectively targeted by BRAF inhibitors. Conversely, targeted therapies have very low or absent activity in patients carrying class 2 and 3 alterations. The spectrum of BRAF alterations in NSCLC patients, and their accompanying clinical features, genomic landscape and treatment outcomes have been poorly reported. PATIENTS AND METHODS: We identified BRAF alterations of defined functional class across different tumors through a systematic review. Then, we selected NSCLC patients carrying BRAF alterations, according to the systematic review, in the cBioPortal (cBioPortal cohort) to collect and analyze clinical, biomolecular and survival data. Finally, we identified NSCLC patients carrying BRAF non-V600 mutations enrolled in POPLAR and OAK trials (POPLAR/OAK cohort), extracting clinical and survival data for survival analyses. RESULTS: 100 different BRAF non-V600 alterations were identified through the systematic review. In the cBioPortal cohort (n = 139), patients harboring class 2 and 3 alterations were more frequently smokers and had higher tumor mutational burden compared to those carrying class 1 alterations. The spectrum of most frequently co-altered genes was significantly different between BRAF alterations classes, including SETD2, STK11, POM121L12, MUC16, KEAP1, TERT, TP53 and other genes. In the POPLAR/OAK cohort, patients carrying non-V600 BRAF alterations were characterized by poor prognosis compared to BRAF wild-type patients. CONCLUSIONS: Different classes of BRAF alterations confer distinctive clinical features, biomolecular signature and disease behavior to NSCLC patients. Non-V600 alterations are characterized by poor prognosis, but key gene co-alterations involved in cancer cell survival and immune pathways may suggest their potential sensitivity to tailored treatments.
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In recent years, immunotherapy has significantly changed the treatment of locally advanced/metastatic non-small-cell lung cancer (NSCLC). Conversely, the role of immunotherapy in NSCLC with uncommon histologies remains unclear, while in other rare thoracic malignancies, such as malignant pleural mesothelioma and thymic epithelial tumors, the use of immune checkpoint inhibitors is modifying therapeutic strategies with solid hopes for the future. However, larger prospective studies are urgently needed to define the best treatment strategies and the role of immunotherapy in these orphan tumors. This review provides a comprehensive overview of the emerging role of immunotherapy in the treatment of patients affected by these rare thoracic malignancies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Torácicas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Prospectivos , Neoplasias Torácicas/tratamiento farmacológico , InmunoterapiaRESUMEN
Epidermal growth factor receptor (EGFR) gene fusions represent an extremely rare aberration, occurring in approximately 0.05-0.13% non-small cell lung cancer (NSCLC) patients. RAD51 is the most frequently involved partner gene in EGFR fusions, but other fusion partner genes have been described. To date, a considerable number of next-generation sequencing (NGS) panels still cannot detect these alterations due to the position of the breakpoint site, mainly involving intron 24 of EGFR. Current evidences show that such gene alteration is more likely to occur in lung adenocarcinomas of young, female, non-smoker patients. Also, brain metastases are frequently reported in these patients. Only very few cases in literature described clinical characteristics and outcomes of patients harboring EGFR gene fusions, reporting responses to 1st generation EGFR tyrosine kinase inhibitors (TKIs). Herein, we report the case of two young non-smoker females with metastatic NSCLC harboring EGFR-RAD51 gene fusion, detected by FoundationOne DX1 assay, who responded to EGFR TKIs. The first patient initially received erlotinib, then switched to osimertinib for renal toxicity, while the second was treated with gefitinib. This is, to our knowledge, the first report describing response to the 3rd EGFR TKI osimertinib. Our experience highlights the need of a broader molecular profiling in young or never smoker NSCLC patients without detectable molecular aberration using standard NGS panels. Finally, further studies to assess the real prevalence of EGFR gene fusions and their spectrum of sensitivity to different EGFR TKIs are needed.
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Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4−8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1−10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies.
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Background: ROS1 fusions are driver molecular alterations in 1-2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. Methods: The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo. Results: 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. Conclusions: The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.
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Vaccine research is a combinatorial science requiring computational analysis of vaccine components, formulations and optimization. We have developed a framework that combines computational tools for the study of immune function and vaccine development. This framework, named ImmunoGrid combines conceptual models of the immune system, models of antigen processing and presentation, system-level models of the immune system, Grid computing, and database technology to facilitate discovery, formulation and optimization of vaccines. ImmunoGrid modules share common conceptual models and ontologies. The ImmunoGrid portal offers access to educational simulators where previously defined cases can be displayed, and to research simulators that allow the development of new, or tuning of existing, computational models. The portal is accessible at
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Sistemas de Computación , Diseño de Fármacos , Sistema Inmunológico/fisiología , Modelos Biológicos , Vacunas , Biología Computacional/métodos , Sistemas de Administración de Bases de Datos , Bases de Datos Factuales , Humanos , Complejo Mayor de Histocompatibilidad , Integración de SistemasRESUMEN
Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a translocation between the PAX3 (or PAX7) and FOXO1 genes. The two main subtypes are fusion-positive alveolar RMS (ARMS) and fusion-negative embryonal RMS (ERMS). This review will focus on the role of receptor tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that is comprised EGFR itself, HER2, HER3 and HER4 in RMS onset and the potential therapeutic targeting of receptor tyrosine kinases. EGFR is highly expressed by ERMS tumors and cell lines, in some cases contributing to tumor growth. If not mutated, HER2 is not directly involved in control of RMS cell growth but can be expressed at significant levels. A minority of ERMS carries a HER2 mutation with driving activity on tumor growth. HER3 is frequently overexpressed by RMS and can play a role in the residual myogenic differentiation ability and in resistance to signaling-directed therapy. HER family members could be exploited for therapeutic approaches in two ways: blocking the HER member (playing a driving role for tumor growth with antibodies or inhibitors) and targeting expressed HER members to vehiculate toxins or immune effectors.
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Diferenciación Celular/fisiología , Regulación Neoplásica de la Expresión Génica/genética , Rabdomiosarcoma/metabolismo , Translocación Genética/fisiología , Diferenciación Celular/genética , Proliferación Celular/fisiología , Humanos , Proteínas Tirosina Quinasas/metabolismo , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/genética , Translocación Genética/genéticaRESUMEN
Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated with the phenomenon. In this review, we propose two factors that have not yet been demonstrated to be directly associated with HP, but upon which it is important to focus attention. IFN-γ is a key cytokine in antitumor response and its levels increase during ICI therapy, whereas CD38 is an alternative immune checkpoint that is involved in immunosuppressive responses. As both factors are associated with resistance to ICI therapy, we have discussed their possible involvement in HPD with the conclusion that IFN-γ may contribute to HP onset through the activation of the inflammasome pathway, immunosuppressive enzyme IDO1 and activation-induced cell death (AICD) in effector T cells, while the role of CD38 in HP may be associated with the activation of adenosine receptors, hypoxia pathways and AICD-dependent T-cell depletion.
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HER2-positive breast cancers may lose HER2 expression in recurrences and metastases. In this work, we studied cell lines derived from two transgenic mammary tumors driven by human HER2 that showed different dynamics of HER2 status. MamBo89HER2stable cell line displayed high and stable HER2 expression, which was maintained upon in vivo passages, whereas MamBo43HER2labile cell line gave rise to HER2-negative tumors from which MamBo38HER2loss cell line was derived. Both low-density seeding and in vitro trastuzumab treatment of MamBo43HER2labile cells induced the loss of HER2 expression. MamBo38HER2loss cells showed a spindle-like morphology, high stemness and acquired in vivo malignancy. A comprehensive molecular profile confirmed the loss of addiction to HER2 signaling and acquisition of an EMT signature, together with increased angiogenesis and migration ability. We identified PDGFR-B among the newly expressed determinants of MamBo38HER2loss cell tumorigenic ability. Sunitinib inhibited MamBo38HER2loss tumor growth in vivo and reduced stemness and IL6 production in vitro. In conclusion, HER2-positive mammary tumors can evolve into tumors that display distinctive traits of claudin-low tumors. Our dynamic model of HER2 status can lead to the identification of new druggable targets, such as PDGFR-B, in order to counteract the resistance to HER2-targeted therapy that is caused by HER2 loss.
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We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.
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Neoplasias de la Mama/metabolismo , Línea Celular Tumoral/metabolismo , Receptor ErbB-2/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/uso terapéutico , Trastuzumab/uso terapéuticoRESUMEN
The prevention of mammary carcinoma by immunological strategies targeting the HER-2/neu receptor has proved to be effective in preclinical models. Thus, a well-characterized HER-2/neu oncogene-driven mammary carcinogenesis model was analysed by various profiling strategies following "triplex" vaccination to identify new candidate targets for breast cancer immunoprevention. 2-DE-based proteomic profiling of preneoplastic and tumour lesions versus normal and aged mammary tissue demonstrated that tumour progression was associated with an up-regulation of molecular chaperones including glucose-regulated protein (GRP)78 and of proteins favouring cell motility, which was in line with the corresponding transcriptomic profiling data. Furthermore, PROTEOMEX analyses suggested that naturally induced autoantibody responses occur during early phases of mammary cancer progression. Most of the cancer progression-induced antibodies targeted proteins of normal and preneoplastic mammary glands. However, three proteins were only recognized by sera obtained from vaccinated mice, including 2 isoforms of annexin A6. The distinct expression patterns for annexin A6 and GRP78 during tumour progression were further verified by western blot and/or immunoprecipitation. In addition, an inhibitor-mediated blockade of GRP78 expression in a model cell line caused a reduced cell growth. Thus, the proteome-based approaches applied in the murine BALB-NeuT model might indeed provide candidates for immunoprevention strategies in breast cancer.
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Modelos Animales de Enfermedad , Neoplasias Mamarias Experimentales/metabolismo , Proteómica/métodos , Receptor ErbB-2/genética , Animales , Anticuerpos Antineoplásicos/sangre , Autoanticuerpos/sangre , Vacunas contra el Cáncer/farmacología , Línea Celular Tumoral , Análisis por Conglomerados , Progresión de la Enfermedad , Electroforesis en Gel Bidimensional , Chaperón BiP del Retículo Endoplásmico , Femenino , Perfilación de la Expresión Génica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Immunoblotting , Inmunoglobulina G/sangre , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Análisis de Componente Principal , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/metabolismo , Reproducibilidad de los ResultadosRESUMEN
Rhabdomyosarcoma is a tumor of striated muscle origin that displays defective myogenic differentiation. Terminal myogenesis switches off cell proliferation and migration, hence, the promotion of rhabdomyosarcoma differentiation should antagonize tumor growth and metastasis. Terminal myogenesis is controlled by cell-intrinsic myogenic transcription factors like myogenin and environmental mediators like interleukin 4 (IL-4). We studied whether the expression of myogenin or exposure to IL-4 could promote the myogenesis of poorly differentiating human rhabdomyosarcoma cells RD/12. Forced expression of myogenin amplified myosin expression and the formation of myotube-like elements, inhibited cell migration, and reduced the growth of local tumors and liver metastases in immunodepressed mice. In contrast, exposure to IL-4 promoted cell proliferation and survival, especially at high cell density, inhibited myogenin expression, and myogenesis. Moreover, IL-4 stimulated the directed migration of cells with low myogenin levels, but not of cells with higher (spontaneous or forced) levels. Thus, IL-4, which was known to promote late stages of normal myogenesis, favors growth and migration, and inhibits further differentiation of the myogenic stages attained by rhabdomyosarcoma cells. Strategies to increase myogenin expression and block IL-4 could simultaneously reduce growth and migration, and enhance terminal differentiation of rhabdomyosarcoma, thus contributing to the control of tumor growth and metastatic spread.
Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular , Interleucina-4/farmacología , Neoplasias Hepáticas/prevención & control , Miogenina/metabolismo , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma Embrionario/prevención & control , Animales , Apoptosis/fisiología , Movimiento Celular/fisiología , Proliferación Celular , Proteínas de Unión al ADN/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Ratones , Ratones Noqueados , Ratones Desnudos , Desarrollo de Músculos , Miogenina/antagonistas & inhibidores , Miogenina/genética , Miosinas/genética , Miosinas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Rabdomiosarcoma Embrionario/metabolismo , Células Tumorales CultivadasRESUMEN
Treatment with inhibition of programmed cell death 1 (PD-1) or its ligand (PD-L1) improves survival in advanced non-small-cell lung cancer (NSCLC). Nevertheless, only a subset of patients benefit from treatment and biomarkers of response to immunotherapy are lacking. Expression of PD-L1 on tumor cells is the primary clinically-available predictive factor of response to immune checkpoint inhibitors, and its relevance in cancer immunotherapy has fostered several studies to better characterize the mechanisms that regulate PD-L1 expression. However, the factors associated with PD-L1 expression are still not well understood. Genomic alterations that activate KRAS, EGFR, and ALK, as well as the loss of PTEN, have been associated with increased PD-L1 expression. In addition, PD-L1 expression is reported to be increased by amplification of CD274, and decreased by STK11 deficiency. Furthermore, PD-L1 expression can be modulated by either tumor extrinsic or intrinsic factors. Among extrinsic factors, the most prominent one is interferon-γ release by immune cells, while there are several tumor intrinsic factors such as activation of the mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Myc pathways that can increase PD-L1 expression. A deeper understanding of PD-L1 expression regulation is crucial for improving strategies that exploit inhibition of this immune checkpoint in the clinic, especially in NSCLC where it is central in the therapeutic algorithm. We reviewed current preclinical and clinical data about PD-L1 expression regulation in NSCLC.
RESUMEN
The TS/A cell line was established in 1983 from a spontaneous mammary tumor arisen in an inbred BALB/c female mouse. Its features (heterogeneity, low immunogenicity and metastatic ability) rendered the TS/A cell line suitable as a preclinical model for studies on tumor-host interactions and for gene therapy approaches. The integrated biological profile of TS/A resulting from the review of the literature could be a path towards the description of a precision experimental model of mammary cancer.