ABSTRACT
Vaccination is considered one of the major milestones in modern medicine, facilitating the control and eradication of life-threatening infectious diseases. Vaccine adjuvants are a key component of many vaccines, serving to steer antigen-specific immune responses and increase their magnitude. Despite major advances in the field of adjuvant research over recent decades, our understanding of their mechanism of action remains incomplete. This hinders our capacity to further improve these adjuvant technologies, so addressing how adjuvants induce and control the induction of innate and adaptive immunity is a priority. Investigating how adjuvant physicochemical properties, such as size and charge, exert immunomodulatory effects can provide valuable insights and serve as the foundation for the rational design of vaccine adjuvants. Most clinically applied adjuvants are particulate in nature and polymeric particulate adjuvants present advantages due to stability, biocompatibility profiles, and flexibility in terms of formulation. These properties can impact on antigen release kinetics and biodistribution, cellular uptake and targeting, and drainage to the lymphatics, consequently dictating the induction of innate, cellular, and humoral adaptive immunity. A current focus is to apply rational design principles to the development of adjuvants capable of eliciting robust cellular immune responses including CD8+ cytotoxic T-cell and Th1-biased CD4+ T-cell responses, which are required for vaccines against intracellular pathogens and cancer. This review highlights recent advances in our understanding of how particulate adjuvants, especially polymer-based particulates, modulate immune responses and how this can be used as a guide for improved adjuvant design.
Subject(s)
Adjuvants, Vaccine , Vaccines , Tissue Distribution , Vaccination , Adaptive Immunity , Adjuvants, Immunologic/pharmacology , AntigensABSTRACT
Stimulator of IFN genes (STING) is a promising target for adjuvants utilized in in situ cancer vaccination approaches. However, key barriers remain for clinical translation, including low cellular uptake and accessibility, STING variability necessitating personalized STING agonists, and interferon (IFN)-independent signals that can promote tumor growth. Here, we identify C100, a highly deacetylated chitin-derived polymer (HDCP), as an attractive alternative to conventional STING agonists. C100 promotes potent anti-tumor immune responses, outperforming less deacetylated HDCPs, with therapeutic efficacy dependent on STING and IFN alpha/beta receptor (IFNAR) signaling and CD8+ T cell mediators. Additionally, C100 injection synergizes with systemic checkpoint blockade targeting PD-1. Mechanistically, C100 triggers mitochondrial stress and DNA damage to exclusively activate the IFN arm of the cGAS-STING signaling pathway and elicit sustained IFNAR signaling. Altogether, these results reveal an effective STING- and IFNAR-dependent adjuvant for in situ cancer vaccines with a defined mechanism and distinct properties that overcome common limitations of existing STING therapeutics.
Subject(s)
Adjuvants, Immunologic , CD8-Positive T-Lymphocytes , Chitin , Membrane Proteins , Mice, Inbred C57BL , Receptor, Interferon alpha-beta , Signal Transduction , Animals , Membrane Proteins/metabolism , Membrane Proteins/immunology , Membrane Proteins/genetics , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Receptor, Interferon alpha-beta/metabolism , Receptor, Interferon alpha-beta/genetics , Mice , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/administration & dosage , Signal Transduction/drug effects , Humans , Cancer Vaccines/immunology , Cancer Vaccines/administration & dosage , Cell Line, Tumor , Female , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/genetics , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/immunology , Neoplasms/immunology , Neoplasms/therapyABSTRACT
Bladder cancer was one of the first to have a successful treatment based on immune system stimulation, recognized by patient survival and tumor recurrence data. In addition, bladder tumors are now known to have high antigenic load and are therefore considered to be susceptible to respond well to new immunotherapies. For these reasons, studying the mechanism of action of bladder cancer immunological-based treatments can provide valuable information both to improve their current use and to under stand why they work in some patients while others do not tolerate this therapy or have tumor progression. In this article, we will focus on the immune response generated by treatment of non-muscle invasive bladder tumors with BCG, as well as the relationship between this knowledge and new immunotherapies. We will first describe the main activities of the immune system, to continue with the treatment of bladder cancer with BCG, its mechanism of action and biomarkers. Finally, we will summarize the observations that led to the useof monoclonal antibody immunotherapy in cancer and will describe some of the new immunotherapies in use to treat bladder cancer patients.
El cáncer vesical fue uno de los primeros en tener un tratamiento de éxito basado en la estimulación del sistema inmunitario, apoyado por los datos de supervivencia de los pacientes y recurrencia de los tumores. Además, hoy día se sabe que los tumores de vejiga presentan alta carga antigénica y, por ello, se considera que son susceptibles de responder favorablemente a las nuevas inmunoterapias. Por estos motivos, estudiar el mecanismo de acción de los tratamientos inmunológicos de cáncer de vejiga nos puede aportar información muy valiosa tanto para mejorar su uso actual como para comprender por qué funcionan en unos pacientes mientras que otros no toleran la terapia o tienen progresión tumoral. En este artículo vamos a centrarnos en la respuesta inmunitaria generada por el tratamiento de los tumores devejiga no-músculo invasivos con BCG, así como la relación entre estos conocimientos y las nuevas inmunoterapias. Para ello, en primer lugar describiremos las principales actividades del sistema inmunitario para continuar con los fundamentos del tratamiento del cáncer devejiga con BCG, su mecanismo de acción y biomarcadores. Por último, recordaremos las observaciones que llevaron al uso de la inmunoterapia con anticuerpos monoclonales en cáncer y describiremos algunas de las nuevas inmunoterapias que se están introduciendo para tratar cánceres vesicales.
Subject(s)
Urinary Bladder Neoplasms , Adjuvants, Immunologic/therapeutic use , Administration, Intravesical , BCG Vaccine/therapeutic use , Biomarkers , Humans , Immunotherapy , Neoplasm Recurrence, Local , Urinary Bladder Neoplasms/drug therapyABSTRACT
The killing of tumor cells by CD8+ T cells is suppressed by the tumor microenvironment, and increased expression of inhibitory receptors, including programmed cell death protein-1 (PD-1), is associated with tumor-mediated suppression of T cells. To find cellular defects triggered by tumor exposure and associated PD-1 signaling, we established an ex vivo imaging approach to investigate the response of antigen-specific, activated effector CD8+ tumor-infiltrating lymphocytes (TILs) after interaction with target tumor cells. Although TIL-tumor cell couples readily formed, couple stability deteriorated within minutes. This was associated with impaired F-actin clearing from the center of the cellular interface, reduced Ca2+ signaling, increased TIL locomotion, and impaired tumor cell killing. The interaction of CD8+ T lymphocytes with tumor cell spheroids in vitro induced a similar phenotype, supporting a critical role of direct T cell-tumor cell contact. Diminished engagement of PD-1 within the tumor, but not acute ex vivo blockade, partially restored cell couple maintenance and killing. PD-1 thus contributes to the suppression of TIL function by inducing a state of impaired subcellular organization.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Neoplasms, Experimental/immunology , Programmed Cell Death 1 Receptor/immunology , Signal Transduction/immunology , T-Lymphocytes, Cytotoxic/immunology , Animals , Cell Communication/immunology , Cell Line, Tumor , Female , Humans , Immunotherapy/methods , Mice, Inbred BALB C , Mice, Transgenic , Microscopy, Fluorescence/methods , Neoplasms, Experimental/pathology , Neoplasms, Experimental/therapy , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/metabolism , Signal Transduction/genetics , Tumor Microenvironment/immunologyABSTRACT
El cáncer vesical fue uno de los primeros en tener un tratamiento de éxito basado en la estimulación del sistema inmunitario, apoyado por los datos de supervivencia de los pacientes y recurrencia de los tumores. Además, hoy día se sabe que los tumores de vejiga presentan alta carga antigénica y, por ello, se considera que son susceptibles de responder favorablemente a las nuevas inmunoterapias. Por estos motivos, estudiar el mecanismo de acción de los tratamientos inmunológicos de cáncer de vejiga nos puede aportar información muy valiosa tanto para mejorar su uso actual como para comprender por qué funcionan en unos pacientes mientras que otros no toleran la terapia o tienen progresión tumoral. En este artículo vamos a centrarnos en la respuesta inmunitaria generada por el tratamiento de los tumores de vejiga no-músculo invasivos con BCG, así como la relación entre estos conocimientos y las nuevas inmunoterapias. Para ello, en primer lugar describiremos las principales actividades del sistema inmunitario para continuar con los fundamentos del tratamiento del cáncer de vejiga con BCG, su mecanismo de acción y biomarcadores. Por último, recordaremos las observaciones que llevaron al uso de la inmunoterapia con anticuerpos monoclonales en cáncer y describiremos algunas de las nuevas inmunoterapias que se están introduciendo para tratar cánceres vesicales
Bladder cancer was one of the first to have a successful treatment based on immune system stimulation, recognized by patient survival and tumor recurrence data. In addition, bladder tumors are now known to have high antigenic load and are therefore considered to be susceptible to respond well to new immunotherapies. For these reasons, studying the mechanism of action of bladder cancer immunological-based treatments can provide valuable information both to improve their current use and to understand why they work in some patients while others do not tolerate this therapy or have tumor progression. In this article, we will focus on the immune response generated by treatment of non-muscle invasive bladder tumors with BCG, as well as the relationship between this knowledge and new immunotherapies. We will first describe the main activities of the immune system to continue with the treatment of bladder cancer with BCG, its mechanism of action and biomarkers. Finally, we will summarize the observations that led to the use of monoclonal antibody immunotherapy in cancer and will describe some of the new immunotherapies in use to treat bladder cancer patients