ABSTRACT
Dendritic cells (DCs) possess a specialized function in presenting antigens and play pivotal roles in both innate and adaptive immune responses. Their ability to cross-present antigens from tumor cells to naïve T cells is instrumental in generating specific T-cell-mediated antitumor responses, crucial for controlling tumor growth and preventing tumor cell dissemination. However, within a tumor immune microenvironment (TIME), the functions of DCs can be significantly compromised. This review focuses on the profile, function, and activation of DCs, leveraging recent studies that reveal insights into their phenotype acquisition, transcriptional state, and functional programs through single-cell RNA sequence (scRNA-seq) analysis. Additionally, the therapeutic potential of DC-mediated tumor antigen sensing in priming antitumor immunity is discussed.
Subject(s)
Dendritic Cells , Immunotherapy , Neoplasms , Tumor Microenvironment , Dendritic Cells/immunology , Humans , Neoplasms/immunology , Neoplasms/therapy , Immunotherapy/methods , Tumor Microenvironment/immunology , Antigens, Neoplasm/immunology , AnimalsABSTRACT
BACKGROUND: Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed. METHODS: We used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations. RESULTS: ICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation. CONCLUSIONS: Our data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.
Subject(s)
Brain Neoplasms/therapy , CTLA-4 Antigen/metabolism , Glioblastoma/therapy , Immune Checkpoint Inhibitors/administration & dosage , Membrane Proteins/administration & dosage , Programmed Cell Death 1 Receptor/metabolism , Animals , Brain Neoplasms/immunology , CTLA-4 Antigen/antagonists & inhibitors , Cell Line, Tumor , Glioblastoma/immunology , Humans , Immune Checkpoint Inhibitors/pharmacology , Membrane Proteins/pharmacology , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , T-Lymphocytes, Regulatory/metabolism , Tumor Escape/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Background: Determine the behavior of the maxillofacial trauma of adults treated in 3 tertiary care centers in the central zone of Chile. Material and Methods: descriptive, cross-sectional, multicenter study, based on the prospective records of maxillofacial trauma cases attended between May 2016 and April 2017 by dental and maxillofacial clinical teams of Adult Emergency Units of hospitals Dr. Sótero del Río (metropolitan region), Carlos Van Buren and Dr. Gustavo Fricke (region V). Age, sex, date of occurrence, type of trauma according to ICD-10, etiology, legal medical prognosis and associated injuries were recorded, stratifying by sex and age. Chi square and unpaired Wilcoxon tests were used to compare by groups. Results: 2.485 cases and 3.285 injuries were investigated. The male: female ratio was 1.7: 1 with age under 30 predominant, followed by older adults. Variability was observed in the yearly, weekly and daily presentation The highest frequencies were in January and September, weekends and at night. The main etiologies were violence (42.3%), falls (13.1%) and road traffic crashes (12.9%) with differences by age and sex (p <0.05). 31,9% of the injuries occurred in hard tissue, being fractures in nasal bones predominant (S02.2). Conclusions: the profile of the maxillofacial trauma in Chile seems to be mixed by age, affecting young people and the elderly. The male sex predominates; the main cause, which varies by age group, is violence. Their surveillance is possible from hospital emergency records
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