ABSTRACT
High-risk Human papillomavirus (HPV) infections represent an important public health issue. Nearly all cervical malignancies are associated with HPV, and a range of other female and male cancers, such as anogenital and oropharyngeal. Aiming to treat HPV-related tumors, our group developed vaccines based on the genetic fusion of the HSV-1 glycoprotein D (gD) with the HPV-16 E7 oncoprotein (gDE7 vaccines). Despite the promising antitumor results reached by gDE7 vaccines in mice, combined therapies may increase the therapeutic effects by improving antitumor responses and halting immune suppressive mechanisms elicited by tumor cells. Considering cancer immunosuppressive mechanisms, indoleamine-2,3-dioxygenase (IDO) enzyme and interleukin-6 (IL-6) stand out in HPV-related tumors. Since IL-6 sustained the constitutive IDO expression, here we evaluated the therapeutic outcomes achieved by the combination of active immunotherapy based on a gDE7 protein-based vaccine with adjuvant treatments involving blocking IDO, either by use of IDO inhibitors or IL-6 knockout mice. C57BL/6 wild-type (WT) and transgenic IL-6-/- mice were engrafted with HPV16-E6/E7-expressing TC-1 cells and treated with 1-methyl-tryptophan isoforms (D-1MT and DL-1MT), capable to inhibit IDO. In vitro, the 1MT isoforms reduced IL-6 gene expression and IL-6 secretion in TC-1 cells. In vivo, the multi-targeted treatment improved the antitumor efficacy of the gDE7-based protein vaccine. Although the gDE7 immunization achieves partial tumor mass control in combination with D-1MT or DL-1MT in WT mice or when administered in IL-6-/- mice, the combination of gDE7 and 1MT in IL-6-/- mice further enhanced the antitumor effects, reaching total tumor rejection. The outcome of the combined therapy was associated with an increased frequency of activated dendritic cells and decreased frequencies of intratumoral polymorphonuclear myeloid-derived suppressor cells and T regulatory cells. In conclusion, the present study demonstrated that IL-6 and IDO negatively contribute to the activation of immune cells, particularly dendritic cells, reducing gDE7 vaccine-induced protective immune responses and, therefore, opening perspectives for the use of combined strategies based on inhibition of IL-6 and IDO as immunometabolic adjuvants for immunotherapies against HPV-related tumors.
Subject(s)
Papillomavirus Infections , Uterine Cervical Neoplasms , Male , Humans , Female , Mice , Animals , Interleukin-6 , Mice, Inbred C57BL , Papillomaviridae , Immunotherapy , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolismABSTRACT
The active immunotherapy concept relies on the use of vaccines that are capable of inducing antitumor immunity, reversion of the suppressive immunological environment, and long-term memory responses. Previously, antitumor vaccines based on a recombinant plasmid (pgDE7h) or a purified protein (gDE7) led to regression of early-established human papillomavirus (HPV)-associated tumors in a preclinical model. In this work, the anticancer vaccines were combined with cisplatin to treat HPV-induced tumors at advanced growth stages. The antitumor effects were evaluated in terms of tumor regression, induction of specific CD8+ T cells, and immune modulation of the tumor microenvironment. Acute toxicity induced by the treatment was measured by weight loss and histological alterations in the liver and kidneys. Our results revealed that the combination of cisplatin with either one of the tested immunotherapies (pgDE7h or gDE7) led to complete tumor regression in mice. Also, the combined treatment resulted in synergistic effects, particularly among mice immunized with gDE7, including activation of systemic and tumor-infiltrating E7-specific CD8+ T cells, tumor infiltration of macrophages and dendritic cells, and prevention of tumor relapses at different anatomical sites. Furthermore, the protocol allowed the reduction of cisplatin dosage and its intrinsic toxic effects, without reducing antitumor outcomes. These results expand our knowledge of active immunotherapy protocols and open perspectives for alternative treatments of HPV-associated tumors.
Subject(s)
Cancer Vaccines/pharmacology , Cisplatin/pharmacology , Neoplasms/drug therapy , Neoplasms/virology , Papillomavirus Infections/complications , Animals , Mice , Mice, Inbred C57BL , Neoplasm Recurrence, Local/prevention & control , Neoplasms/immunology , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To analyze the risks related to vaccines and the impacts of non-vaccination on the world population. METHODS: This is a narrative review that has considered information present in the bibliographic databases NCBI-PubMed, Medline, Lilacs, and Scientific Electronic Library Online (SciELO), between November 2015 and November 2016. For the analysis of outbreaks caused by non-vaccination, we considered the work published between 2010 and 2016. RESULTS: We have described the main components of the vaccines offered by the Brazilian public health system and the adverse events associated with these elements. Except for local inflammatory reactions and rare events, such as exacerbation of autoimmune diseases and allergies, no causal relationship has been demonstrated between the administration of vaccines and autism, Alzheimer's disease, or narcolepsy. On the other hand, the lack of information and the dissemination of non-scientific information have contributed to the reemergence of infectious diseases in several countries in the world and they jeopardize global plans for the eradication of these diseases. CONCLUSIONS: The population should be well informed about the benefits of vaccination and health professionals should assume the role of disseminating truthful information with scientific support on the subject, as an ethical and professional commitment to society.
Subject(s)
Medication Adherence , Vaccination/adverse effects , Vaccines/adverse effects , Adverse Drug Reaction Reporting Systems , Brazil , Female , Humans , Male , National Health Programs , Risk Factors , Vaccination/statistics & numerical dataABSTRACT
ABSTRACT OBJECTIVE: To analyze the risks related to vaccines and the impacts of non-vaccination on the world population. METHODS: This is a narrative review that has considered information present in the bibliographic databases NCBI-PubMed, Medline, Lilacs, and Scientific Electronic Library Online (SciELO), between November 2015 and November 2016. For the analysis of outbreaks caused by non-vaccination, we considered the work published between 2010 and 2016. RESULTS: We have described the main components of the vaccines offered by the Brazilian public health system and the adverse events associated with these elements. Except for local inflammatory reactions and rare events, such as exacerbation of autoimmune diseases and allergies, no causal relationship has been demonstrated between the administration of vaccines and autism, Alzheimer's disease, or narcolepsy. On the other hand, the lack of information and the dissemination of non-scientific information have contributed to the reemergence of infectious diseases in several countries in the world and they jeopardize global plans for the eradication of these diseases. CONCLUSIONS: The population should be well informed about the benefits of vaccination and health professionals should assume the role of disseminating truthful information with scientific support on the subject, as an ethical and professional commitment to society.
RESUMO OBJETIVO: Analisar os riscos relacionados às vacinas e os impactos da não vacinação para a população mundial. MÉTODOS: Revisão narrativa que considerou informações contidas nas bases de dados bibliográficos NCBI-PubMed, Medline, Lilacs e Scientific Electronic Library Online (SciELO), no período compreendido entre novembro de 2015 e novembro de 2016. Para a análise de surtos ocasionados pela não vacinação foram considerados os trabalhos publicados entre 2010 e 2016. RESULTADOS: Foram descritos os principais componentes das vacinas oferecidas pelo sistema público de saúde brasileiro e eventos adversos associados a esses elementos. Com exceção de reações inflamatórias locais e efeitos raros como exacerbação de doenças autoimunes e alergias, não foi demonstrada relação causal entre a administração de vacinas e autismo, mal de Alzheimer ou narcolepsia. Por outro lado, a falta de informações e a divulgação de informações não científicas têm contribuído para a reemergência de doenças infecciosas em diversos países no mundo e põe em risco planos globais para a erradicação de doenças infecciosas. CONCLUSÕES: A população deve estar bem informada quanto aos benefícios da vacinação e os profissionais da saúde devem assumir o papel de divulgar informações verídicas e com respaldo científico sobre o tema, como compromisso ético e profissional junto à sociedade.
Subject(s)
Humans , Male , Female , Vaccination/adverse effects , Medication Adherence , Brazil , Vaccines/adverse effects , Risk Factors , Vaccination/statistics & numerical data , Adverse Drug Reaction Reporting Systems , National Health ProgramsABSTRACT
OBJECTIVE: To analyze the risks related to vaccines and the impacts of non-vaccination on the world population. METHODS: This is a narrative review that has considered information present in the bibliographic databases NCBI-PubMed, Medline, Lilacs, and Scientific Electronic Library Online (SciELO), between November 2015 and November 2016. For the analysis of outbreaks caused by non-vaccination, we considered the work published between 2010 and 2016. RESULTS: We have described the main components of the vaccines offered by the Brazilian public health system and the adverse events associated with these elements. Except for local inflammatory reactions and rare events, such as exacerbation of autoimmune diseases and allergies, no causal relationship has been demonstrated between the administration of vaccines and autism, Alzheimer's disease, or narcolepsy. On the other hand, the lack of information and the dissemination of non-scientific information have contributed to the reemergence of infectious diseases in several countries in the world and they jeopardize global plans for the eradication of these diseases. CONCLUSIONS: The population should be well informed about the benefits of vaccination and health professionals should assume the role of disseminating truthful information with scientific support on the subject, as an ethical and professional commitment to society.
ABSTRACT
OBJECTIVE: To analyze the risks related to vaccines and the impacts of non-vaccination on the world population. METHODS: This is a narrative review that has considered information present in the bibliographic databases NCBI-PubMed, Medline, Lilacs, and Scientific Electronic Library Online (SciELO), between November 2015 and November 2016. For the analysis of outbreaks caused by non-vaccination, we considered the work published between 2010 and 2016. RESULTS: We have described the main components of the vaccines offered by the Brazilian public health system and the adverse events associated with these elements. Except for local inflammatory reactions and rare events, such as exacerbation of autoimmune diseases and allergies, no causal relationship has been demonstrated between the administration of vaccines and autism, Alzheimer's disease, or narcolepsy. On the other hand, the lack of information and the dissemination of non-scientific information have contributed to the reemergence of infectious diseases in several countries in the world and they jeopardize global plans for the eradication of these diseases. CONCLUSIONS: The population should be well informed about the benefits of vaccination and health professionals should assume the role of disseminating truthful information with scientific support on the subject, as an ethical and professional commitment to society.
OBJETIVO: Analisar os riscos relacionados às vacinas e os impactos da não vacinação para a população mundial. MÉTODOS: Revisão narrativa que considerou informações contidas nas bases de dados bibliográficos NCBI-PubMed, Medline, Lilacs e Scientific Electronic Library Online (SciELO), no período compreendido entre novembro de 2015 e novembro de 2016. Para a análise de surtos ocasionados pela não vacinação foram considerados os trabalhos publicados entre 2010 e 2016. RESULTADOS: Foram descritos os principais componentes das vacinas oferecidas pelo sistema público de saúde brasileiro e eventos adversos associados a esses elementos. Com exceção de reações inflamatórias locais e efeitos raros como exacerbação de doenças autoimunes e alergias, não foi demonstrada relação causal entre a administração de vacinas e autismo, mal de Alzheimer ou narcolepsia. Por outro lado, a falta de informações e a divulgação de informações não científicas têm contribuído para a reemergência de doenças infecciosas em diversos países no mundo e põe em risco planos globais para a erradicação de doenças infecciosas. CONCLUSÕES: A população deve estar bem informada quanto aos benefícios da vacinação e os profissionais da saúde devem assumir o papel de divulgar informações verídicas e com respaldo científico sobre o tema, como compromisso ético e profissional junto à sociedade