Metabolic Immunosuppression Research Articles

Immune profiling and immunotherapeutic targets in pancreatic cancer.

BackgroundImmunotherapeutic approaches for pancreatic ductal adenocarcinoma (PDAC) are less successful as compared to many other tumor types. In this study, comprehensive immune profiling was performed in order to identify novel, potentially actionable targets for immunotherapy.MethodsFormalin-fixed paraffin embedded (FFPE) specimens from 68 patients were evaluated for expression of 395 immune-related markers (RNA-seq), mutational burden by complete exon sequencing of 409 genes, PD-L1 expression by immunohistochemistry (IHC), pattern of tumor infiltrating lymphocytes (TILs) infiltration by CD8 IHC, and PD-L1/L2 copy number by fluorescent in situ hybridization (FISH).ResultsThe seven classes of actionable genes capturing myeloid immunosuppression, metabolic immunosuppression, alternative checkpoint blockade, CTLA-4 immune checkpoint, immune infiltrate, and programmed cell death 1 (PD-1) axis immune checkpoint, discerned 5 unique clinically relevant immunosuppression expression profiles (from most to least common): (I) combined myeloid and metabolic immunosuppression [affecting 25 of 68 patients (36.8%)], (II) multiple immunosuppressive mechanisms (29.4%), (III) PD-L1 positive (20.6%), (IV) highly inflamed PD-L1 negative (10.3%); and (V) immune desert (2.9%). The Wilcoxon rank-sum test was used to compare the PDAC cohort with a comparison cohort (n=1,416 patients) for the mean expressions of the 409 genes evaluated. Multiple genes including TIM3, VISTA, CCL2, CCR2, TGFB1, CD73, and CD39 had significantly higher mean expression versus the comparison cohort, while three genes (LAG3, GITR, CD38) had significantly lower mean expression.ConclusionsThis study demonstrates that a clinically relevant unique profile of immune markers can be identified in PDAC and be used as a roadmap for personalized immunotherapeutic decision-making strategies.

Structural analysis of morphometric and morphofunctional state of immunocompetent blood cells in case of purulent inflammatory diseases of soft tissues on the background of type 2 diabetes

Background. According to the research results, patients with type 2 diabetes have steady changes in various parts of the immune system: cellular, humoral, phagocytic activity. Hyperglycemia, hyperlipidemia, insulin resistance, and adaptive hyperinsulinemia affect the cells of the immune system leading to the development of metabolic immunosuppression and forming a stable immunological disorder. The purpose of the research is to study the morphometric and morphofunctional state of peripheral blood leukocytes in patients with type 2 diabetes in order to determine their significance in the development of purulent inflammatory diseases of soft tissues. Materials and methods. In this work, an analysis was carried out of morphometric, cytohistochemical and laboratory findings of the control (20 healthy volunteers) and the main group (47 patients with suppurative soft tissue diseases on the background of type 2 diabetes), with the statistical proces­sing of the obtained data. Results. The study of morphofunctional features of nonspecific and specific defense cells in purulent inflammatory diseases of soft tissues on the background of type 2 diabetes showed that the main cause of diabetic complications are the revealed changes in the bactericidal activity of segmented neutrophils. The trend of white blood cell differential indicators and the distribution curve of mononuclear cells by size, as well as the growth of the lymphocytic-granulocytic index indicate a chronic formation of endotoxins on the background of type 2 diabetes. Conclusions. Lowering the level of cationic neutrophil proteins, the activity of myeloperoxidase and the nitroblue tetrazolium test under stimulation of neutrophil granulocytes by lectins is a sign of unsatisfactory state of the bactericidal cell system, which may be the cause of chronic and acute inflammatory processes in the body that accompany type 2 diabetes leading to a functional exhaustion of the macrophage link of the immune defense.

Results of cytochemical investigation of neutrophil granulocytes in patients with purulent-inflammatory diseases of fine tissues on the type 2 diabetes mellitus

Patients with purulent-inflammatory diseases of soft tissues on the background of diabetes type 2 are resistant changes in various parts of the immune system. Hyperglycemia, hyperlipidemia, insulin resistance and adaptive hyperinsulinemia affect the cells of the immune system, promote the development of metabolic immunosuppression with the formation of stable immune dysfunction. The purpose of the study to investigate and analyze the metabolic state of immunocompetent cells in patients with purulent-inflammatory diseases of soft tissues on the background of DMD type 2. The study was conducted in 47 patients (the main group) with purulent-inflammatory diseases of soft-tissue on the background of diabetes mellitus, and 20 healthy volunteers (the comparison group) using the cytohistochemical restoration method of NST based on the percentage composition of neutrophils that have cytoplasm of formazan granules. The spontaneous neutrophil response was studied, as well as the parameters of the NST-test in stimulation of neutrophil granulocytes in vitro to assess the bactericidal, resource potential and their ability to complete phagocytosis. Results of the study showed that the decrease in the activity of myeloperoxidase and the NST-test in the conditions of stimulation of neutrophil granulocytes is a sign of unsatisfactory state of the bactericidal system of cells, which may be the cause of acute inflammatory processes in the body that accompany type 2 diabetes, which leads to functional exhaustion of the macrophage level of the immune body protection. At GZZMT against the background of DM 2 type compared with the norm, the “spontaneous” NST-test of neutrophils is high, which is due to the presence of inflammatory process. The index of stimulation of neutrophils is lower in the main group (1.6 times: 5.3±0.2% in the main group versus 8.4±0.4% in the control, p≤0.05), which is an indicator of a relatively weaker stimulation of those populations of neutrophils that were responsible for high indices in the “spontaneous” NST test, and the impaired state of cellular metabolism. So, in patients with type 2 diabetes, a violation of the bactericidal system of organism protection, which is one of the causes of the development of infectious and inflammatory processes.