Recent Advancements in the Mechanisms Underlying Resistance to PD-1/PD-L1 Blockade Immunotherapy

Release of immunoreactive negative regulatory factors such as immune checkpoint limits antitumor responses. PD-L1 as a significant immunosuppressive factor has been involved in resistance to therapies such as chemotherapy and target therapy in various cancers. Via interacting with PD-1, PD-L1 can regulate other factors or lead to immune evasion of cancer cells. Besides, immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in the different tumors, but a significant percentage of patients cannot benefit from this therapy due to primary and acquired resistance during treatment. In this review, we described the utility of PD-L1 expression levels for predicting poor prognosis in some tumors and present evidence for a role of PD-L1 in resistance to therapies through PD-1/PD-L1 pathway and other correlating signaling pathways. Afterwards, we elaborate the key mechanisms underlying resistance to PD-1/PD-L1 blockade in cancer immunotherapy. Furthermore, promising combination of therapeutic strategies for patients resistant to PD-1/PD-L1 blockade therapy or other therapies associated with PD-L1 expression was also summarized.

Leukocyte profile of the helmeted manakin, Antilophia galeata (Passeriformes: Pipridae) in a Cerrado forest fragment

Changes in the amounts and proportions of leukocytes, known as leucocyte profiles, have been documented for several bird species and have been used to measure stress levels in these animals. The present work ascertained the biological and ecological attributes that influence the leukocyte profile of Antilophia galeata (Lichtenstein, 1823), the helmeted manakin. This species has been deemed useful in ecological studies because it responds to environmental changes. Blood samples drawn from 89 individuals of A. galeata captured in a Cerrado forest fragment were subjected to analysis under optical microscopy to identify and quantify leukocytes and micronuclei. The number of lymphocytes was greater for males, non-reproductive individuals and individuals infected with ticks. None of the leukocyte components differed in relation to age, molting or body condition index. The amount of micronuclei was correlated with values for total leukocytes, H/L ratio, heterophils, basophils and monocytes. The results suggest that reproduction may be an immunosuppressive factor for the species, producing sexual differences in lymphocyte availability. In addition, biomarkers of genotoxic damage (micronuclei) were related to the amount of leukocytes, indicating that individuals may be sensitive to environmental disturbances. Leukocyte profiles can be considered a useful tool for addressing ecological questions that are relevant to the conservation of species in degraded environments.

Cryptococcus neoformans meningitis in an immunocompetent adult: A case report

Neuromeningeal cryptococcosis (NMC) is relatively rare in immunocompetent subjects. We report a Congolese case of NMC diagnosed in an apparently immunocompetent subject. A 35-year-old woman was admitted for acute meningoencephalitis. The cerebrospinal fluid (CSF) examination revealed cytological and biochemical abnormalities and the presence of Cryptococcus neoformans on direct examination with India ink and in culture. The serum dosage of cryptococcal antigens was titrated at 1:32. HIV and syphilis antibodies were negative and the blood CD4 lymphocyte count was 610/mm3. The patient had no other immunosuppressive factors, in particular no hematologic abnormalities, no solid tumor, or malnutrition. She was unsuccessfully treated with fluconazole intraveinously, and died after 10 days of treatment. This observation reminds us that NMC can occur in subjects without apparent immunosuppressive factor with a misleading clinical presentation. It is a rare infection with a severe prognosis even in immunocompetent patients.

SEMAPHORIN 3A - A NEW INTRATHYMIC SUPPRESSOR FACTOR

Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several semaphorins, so-called ‘immune semaphorins’, are also involved in various phases of immune responses. One of such factors is semaphorin 3A - a member of class 3 semaphorins, which are secretory molecules in vertebrates. There are multiple mechanisms involved in the process of semaphorin 3A-mediated regulation. One of them is down-regulation of peripheral T-cell activity in consequence of which semaphorin 3A is considered as an immunosuppressive factor. But semaphorin 3A is also expressed in the thymus while its function there remains obscure. Here are discussed new data on immunosuppressive function of this factor towards thymocytes and thymic epithelial cells, obtained in vitro. Because it is involved both in physiological immunoregulation and in the pathogenesis of many autoimmune, atopic, and malignant diseases, semaphorin 3A turns to be a promising therapeutic tool to be studied and applied in these diseases.

Effects of X-Ray Exposure on Some CMI Regulatory Cytokines in Technicians Serum Samples

Ionizing radiation considered as an immunosuppressive factor upon over dose of exposure. Radiation field workers usually following a periodic checkup to monitor changes in their clinical status. Cell Mediated Immunity (CMI) has an important cytokines that regulate this specific immunological process. This study estimated the Interleukins (IL-2, IL-12 and IL-18) levels in serum samples using ELISA technique. Serum samples were collected from X-ray Technicians (Radiography, Fluoroscopy and Computed Tomography Scan Technicians) working in AL-Muthanna governorate hospitals. A total of (60) technicians and (30) control were involved in this research. Results showed significant decrease in IL-2 levels and increase in IL-18 levels in test groups (technicians) as compared with controls. While, IL-12 levels did not show a difference; all obtained values were within normal range. Overdose of X-ray exposure caused CMI suppression via disturbing the levels of critical cytokines (IL-2 and IL-18) leading to CMI loss regulation.

Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases

Interleukin-37 (IL-37) is an IL-1 family cytokine discovered in recent years and has 5 different isoforms. As an immunosuppressive factor, IL-37 can suppress excessive immune response. IL-37 plays a role in protecting the body against endotoxin shock, ischemia-reperfusion injury, autoimmune diseases, and cardiovascular diseases. In addition, IL-37 has a potential antitumor effect. IL-37 and its receptors may serve as novel targets for the study, diagnosis, and treatment of immune-related diseases and tumors.

Uniform Persistence and Global Stability for a Brain Tumor and Immune System Interaction

This paper describes the synergistic interaction between the growth of malignant gliomas and the immune system interactions using a system of coupled ordinary differential equations (ODEs). The proposed mathematical model comprises the interaction of glioma cells, macrophages, activated Cytotoxic T-Lymphocytes (CTLs), the immunosuppressive factor TGF-[Formula: see text] and the immuno-stimulatory factor IFN-[Formula: see text]. The dynamical behavior of the proposed system both analytically and numerically is investigated from the point of view of stability. By constructing Lyapunov functions, the global behavior of the glioma-free and the interior equilibrium point have been analyzed under some assumptions. Finally, we perform numerical simulations in order to illustrate our analytical findings by varying the system parameters.