ABSTRACT
Breast cancer is one of the leading causes of death that affects the female population worldwide. Despite advances in treatments and a greater understanding of the disease, there are still difficulties in successfully treating patients. Currently, the main challenge in the field of cancer vaccines is antigenic variability which can reduce antigen-specific T- cell response efficacy. The search for and validation of immunogenic antigen targets increased dramatically over the past few decades and, with the advent of modern sequencing techniques, permitting the fast and accurate identification of the neoantigen landscape of tumor cells, will undoubtedly continue to grow exponentially for years to come. We have previously implemented Variable Epitope Libraries (VEL) as an unconventional vaccine strategy in preclinical models and for identifying and selecting mutant epitope variants. Here, we used an alanine-based sequence to generate a 9-mer VEL-like combinatorial mimotope library G3d as a new class of vaccine immunogen. An in silico analysis of the 16,000 G3d-derived sequences revealed potential MHC-I binders and immunogenic mimotopes. We demonstrated the antitumor effect of treatment with G3d in the 4T1 murine model of breast cancer. Moreover, two different T cell proliferation screening assays against a panel of randomly selected G3d-derived mimotopes allowed the isolation of both stimulatory and inhibitory mimotopes showing differential therapeutic vaccine efficacy. Thus, the mimotope library is a promising vaccine immunogen and a reliable source for isolating molecular cancer vaccine components.
Subject(s)
Neoplasms , Peptide Library , Female , Animals , Mice , Epitopes , Disease Models, Animal , Antigens, NeoplasmABSTRACT
The identification of novel targets for cancer immunotherapy and the development of new vaccine immunogens are subjects of permanent interest. MUC1 is an overexpressed antigen found in most tumors, and its overexpression correlates with poor prognosis. Many attempts to direct the immune response against MUC1 in tumor cells have failed, including several clinical trials. We have previously developed an innovative Variable Epitope Library (VEL) vaccine platform that carries massively substituted mutant variants of defined epitopes or epitope regions as an alternative to using wild-type peptide sequences-based immunogens. Here, two murine MUC1-derived epitopes equivalent to the previously tested in cancer immunotherapy human MUC1 regions were used to generate VELs. We observed that vaccination with the 23L VEL immunogens, encompassing the entire signal peptide region of MUC1, reduces the tumor area compared to the wild-type sequence treatment. Contrastingly, vaccination with the MUC1 signal peptide-derived predicted CD8++ T cell epitope-based VEL, 9MUC1spL, showed similar tumor area reduction as the wild-type treatment; however, a decrease in lung metastasis after 9MUC1spL treatment was observed. In addition, vaccination induced a large pool of CD8+ T cells which recognized most variant epitopes from 9MUC1spL. Also, we generated MUC1 variable number tandem repeat (VNTR)-based VELs that reduced the metastatic burden when dendritic cells and M13 recombinant bacteriophages were used as vaccine carriers. Collectively, our data demonstrate the immunogenic and antitumor properties of MUC1 signal peptide- and VNTR-derived VEL immunogens.
Subject(s)
Breast Neoplasms , Cancer Vaccines , Animals , Breast Neoplasms/genetics , Breast Neoplasms/therapy , CD8-Positive T-Lymphocytes , Disease Models, Animal , Epitopes, T-Lymphocyte/genetics , Female , Humans , Mice , Mucin-1/genetics , Protein Sorting SignalsABSTRACT
After decades of cancer vaccine efforts, there is an imperious necessity for novel ideas that may result in better tumor control in patients. We have proposed the use of a novel Variable Epitope Library (VEL) vaccine strategy, which incorporates an unprecedented number of mutated epitopes to target antigenic variability and break tolerance against tumor-associated antigens. Here, we used an oncofetal antigen/immature laminin receptor protein-derived sequence to generate 9-mer and 43-mer VEL immunogens. 4T1 tumor-bearing mice developed epitope-specific CD8+IFN-γ+ and CD4+IFN-γ+ T cell responses after treatment. Tumor and lung analysis demonstrated that VELs could increase the number of tumor-infiltrating lymphocytes with diverse effector functions while reducing the number of immunosuppressive myeloid-derived suppressor and regulatory T cells. Most importantly, VEL immunogens inhibited tumor growth and metastasis after a single dose. The results presented here are consistent with our previous studies and provide evidence for VEL immunogens' feasibility as promising cancer immunotherapy.
Subject(s)
Antigens, Neoplasm/immunology , Breast Neoplasms , Cancer Vaccines/immunology , Epitopes, T-Lymphocyte/immunology , Receptors, Laminin/immunology , Animals , Cancer Vaccines/pharmacology , Disease Models, Animal , Epitope Mapping/methods , Female , Mice , Mice, Inbred BALB CABSTRACT
Antibodies, T cell receptors and major histocompatibility complex molecules are members of the immunoglobulin superfamily and have pivotal roles in the immune system. The fine interrelation between them regulates several immune functions. Here, we describe lesser-known functions ascribed to these molecules in generating and maintaining immune response. Particularly, we outline the contribution of antibody- and T cell receptor-derived complementarity-determining region neoantigens, antigenized antibodies, as well as major histocompatibility complex class I molecules-derived epitopes to the induction of protective/therapeutic immune responses against pathogens and cancer. We discuss findings of our own and other studies describing protective mechanisms, based on immunogenic properties of immunoglobulin superfamily members, and evaluate the perspectives of application of this class of immunogens in molecular vaccines design.
Subject(s)
Antibodies/immunology , Major Histocompatibility Complex/immunology , Receptors, Antigen, T-Cell/immunology , Amino Acid Sequence/genetics , Animals , Antibody Formation , Epitopes/immunology , Histocompatibility Antigens Class I/immunology , Humans , Immunity/immunology , Immunoglobulin Heavy Chains , Immunoglobulin Variable Region , Immunoglobulins/immunology , Immunoglobulins/metabolismABSTRACT
Immune tolerance is the main challenge in the field of cancer vaccines, so modified peptide sequences or naturally occurring mutated versions of cancer-related wild-type (WT) antigens represent a promising pathway. However, the low immunogenicity of mutation-induced neoantigens and, particularly, their incapacity to activate CD8+ T cells are generating doubts on the success of neoantigen-based cancer vaccines in clinical trials. We developed a novel vaccine approach based on a new class of vaccine immunogens, called variable epitope libraries (VELs). We used three regions of survivin (SVN), composed of 40, 49 and 51 amino acids, along with the complete SVN protein to generate the VELs as multiepitope vaccines. BALB/c mice, challenged with the aggressive and highly metastatic 4T1 cell line, were vaccinated in a therapeutic setting. We showed significant tumor growth inhibition and, most importantly, strong suppression of lung metastasis after a single immunization using VEL vaccines. We demonstrated vaccine-induced broad cellular immune responses concomitant with extensive tumor infiltration of T cells, the activation of CD107a+ IFN-γ+ T cells in the spleen and a significant increase in the number of CD3+ CD8+ Ly6C+ effector T cells. In addition, we observed the presence of interferon-γ-, granzyme B- and perforin-producing lymphocytes along with modifications in the amount of CD11b+ Ly6Cint/low Ly6G+ granulocytic myeloid-derived suppressor cells and CD4+ CD25+ FoxP3+ regulatory T cells in the lungs and tumors of mice. In summary, we showed that the VELs represent a potent new class of cancer immunotherapy and propose the application of the VEL vaccine concept as a true alternative to currently available vaccine platforms.
Subject(s)
Breast Neoplasms/immunology , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/immunology , Epitopes, T-Lymphocyte/immunology , Immunotherapy/methods , Lymphocytes, Tumor-Infiltrating/immunology , Myeloid-Derived Suppressor Cells/immunology , Survivin/metabolism , T-Lymphocytes, Regulatory/immunology , Animals , Cell Line, Tumor , Disease Models, Animal , Female , Forkhead Transcription Factors/metabolism , Humans , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Peptide Library , Survivin/genetics , Survivin/immunology , VaccinationABSTRACT
Although various immune checkpoint inhibitors (ICIs), used for the treatment of advanced cancer, showed remarkably durable tumor regression in a subset of patients, there are important limitations in a large group of non-responders, and the generation of novel immunogens capable of inducing protective cellular immune responses is a priority in cancer immunotherapy field. During the last decades, several types of vaccine immunogens have been used in numerous preclinical studies and clinical trials. However, although immunity to tumor Ags can be elicited by most vaccines tested, their clinical efficacy remains modest. Recently, we have developed an innovative vaccine concept, called Variable Epitope Libraries (VELs), with the purpose to exploit the high antigenic variability of many important pathogens and tumor cells as starting points for the construction of a new class of vaccine immunogens capable of inducing the largest possible repertoire of both B and T cells. In the present study, we decided to generate VEL immunogens derived from both classical and non-classical major histocompatibility complex (MHC) class I molecules. The MHC molecules, responsible for antigen presentation and subsequent activation of T lymphocytes, undergo multiple modifications that directly affect their proper function, resulting in immune escape of tumor cells. Two large VELs derived from multi-epitope region of H2-Kd and Qa-2 sequences (46 and 34 amino acids long, respectively), along with their wild type counterparts have been generated as synthetic peptides and tested in an aggressive 4T1 mouse model of breast cancer. Significant inhibition of tumor growth and the reduction of metastatic lesions in the lungs of immunized mice were observed. This study demonstrated for the first time the successful application of VELs carrying combinatorial libraries of epitope variants derived from MHC class I molecules as novel vaccine immunogens.
Subject(s)
Cancer Vaccines/immunology , Epitopes/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Animals , Cancer Vaccines/genetics , Cell Proliferation , Disease Models, Animal , Epitopes/genetics , Female , Gene Library , Humans , Immunity , Mice , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , VaccinationABSTRACT
Presenta un recuento histórico del establecimiento y evolución del Consejo de Salubridad General. Contenido: I) Actividades y reformas durante el período de 1935-1983: 1) Una laguna histórica; 2) Hacia una institución revolucionaria; el gobierno de Lázaro Cárdenas;3) Bajo la presidencia del General Manuel Avila Camacho: creación de la Secretaría de Salubridad y Asistencia y reorganización del Consejo de Salubridad General; 4) Un período incierto que culmina en la expedición de un nuevo reglamento para el Consejo: reglamento de 1951; 5) La gestión de Ignacio Morones Prieto frente al Consejo: modificaciones de acuerdo con el Código Sanitario de 1955; 6) El Consejo como un órgano anacrónico; 7) Funcionamiento incipiente del Consejo de Salubridad General; 8) El presidente Luis Echeverría da su aval al Consejo de Salubridad General: reglamento interior 1974; 9) Un período de gran actividad que redundaría en cambios trascendentes; 10) Realización de un profundo cambio: los insumos del sector salud. II) Explicación y comprensión históricas de lo tratado en la obra: 11) Factores y circunstancias que hicieron posible la creación del Consejo de Salubridad General del Departamento de México; 12) El Consejo de Salubridad del Departamento no surgió de la nada: el protomedicato; la Facultad Médica del Distrito federal; 13) Factores y circunstancias que explican la creación del Consejo de Salubridad General del Departamento de México; 14) El Consejo Central de Salubridad; 15) De 1872 a la crisis del Consejo Superior de Salubridad del Distrito Federal de 1877; 16) El Consejo Superior de Salubridad y el Código Sanitario de 1891; 17) La transformación del Consejo Superior de Salubridad en el Consejo de Salubridad General y la creación del Departamento de Salubridad; 18) La Secretaría de Salud y el renacimiento del Consejo de Salubridad General. III) El resurgimiento del Consejo de Salubridad General. Anexos
Subject(s)
Health Policy , Public HealthABSTRACT
Corresponde a las actividades del Consejo de Salubridad General a partir del gobierno cardenista, haciendo referencia a los años que transcurren desde que éste se establece, hasta la década de los ochenta. Ofrece una visión del presente y el futuro del Consejo, haciendo un recuento de las tareas efectuadas de 1995 al año 2000. (AU)
Subject(s)
Public Health/history , Health Councils/history , Public Administration/history , Health Care Reform/history , MexicoABSTRACT
Retoma el relato en el momento inmediato posterior al movimento revolucionario. Relata las actividades en que participa el Consejo compartiendo responsabilidades con el recién creado Departamento de Salubridad. (AU)
Subject(s)
Humans , Public Health/history , Health Councils/history , Hygiene/history , Congresses as Topic/history , MexicoABSTRACT
Se relatan las acciones que desarrolló el Consejo Superior de Salubridad en su transición hacia el Consejo de Salubridad General, y se analiza la política de salud que en esa etapa se aplicaban. El contenido del libro se sitúa en el período 1917-1926, principalmente. Los capítulos que integran la obra son: Prólogo. 1) Política y salubridad. 2) Conocimientos y posición social del médico dedicado a la salubridad. 3) El período de transformación y la organización de la salubridad en el México post-revolucionario. 4) Los congresos nacionales del Tabardillo. 5) La salud pública en los tiempos de Obregón. 6) El VI Congreso Médico Nacional y la salubridad. 7) Reglamento del Consejo Superior de Salubridad del Distrito Federal. 8) Situación de las distintas autoridades sanitarias del país. La primera convención sanitaria. 9) Primera convención de delegados del Departamento de Salubridad Pública en puertos y fronteras. 10) La nueva época del boletín, primero del Consejo Superior de Salubridad y ahora del Departamento de Salubridad. 11) La escuela de salubridad. 12) Excitativas del Primer Congreso Mexicano del Niño al Consejo Superior de Salubridad. 13) El día de la tuberculosis, el proyecto del Parque Nacional de Higiene y el armamento tuberculoso mexicano. 14) Comisión Especial para la Campaña contra la Fiebre Amarilla. 15) La influenza y las uncinariasis. 16) Alcoholismo, sífilis y tuberculosis, grandes problemas de salud pública. 17) Muere un historiador del Consejo Superior de Salubridad cuya obra desconocemos. 18) Un caso de nepotismo y ciertos malos manejos. 19) El comercio y adicción a las drogas heroicas es un asunto de la salud pública. 20) Vamos poniendo las cosas en claro
Subject(s)
Health Policy , Public HealthABSTRACT
La historia del Consejo Superior de Salubridad es la historia de la institución encargada del cuidado de la salud o higiene públicas, abarcando también, en un largo periodo, la autorización y vigilancia del ejercicio de las profesiones médicas y paramédicas, durante varias décadas del siglo XIX y los primeros diez y seis años del siglo XX. La historia del Consejo Superior de Salubridad - si se trata de una verdadera historia y no de una simple recopilación de documentos - debe permitirnos entender lo que en la época a la que se limita nuestro estudio fue para el Estado mexicano y las ciencias médicas, la salud o higiene públicas; debe permitirnos conocer cual fue su importancia social, política y económica, el lugar que ocupaba en la enseñanza de la medicina y en el interés de los médicos, etc. (AU)
Subject(s)
History, 20th Century , Public Health , Health Councils , Sanitary Management , Communicable Disease Control , MexicoABSTRACT
Investigación que muestra la historia de la salubridad pública, las enfermedades contagiosas y el ejercicio de la medicina en la ciudad de México, de acuerdo al Consejo Superior de Salubridad. Dicho documento comprende desde la creación del Consejo hasta finales del siglo XIX, a partir de los siguientes capítulos: I. Prólogo II. Agradecimientos y una aclaración sobre las referencias III. Presentación IV. Centralismo y federalismo V. Segundo Imperio VI. La República restaurada
