Data from Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes
Malte MohmeSimon SchliffkeCécile L. MaireAlessandra RüngerLaura GlauKlaus C. MendeJakob MatschkeChristina GehbauerNuray AkyüzSvenja ZapfMareike HolzMiriam SchaperTobias MartensNils Ole SchmidtSven PeineManfred WestphalMascha BinderEva TolosaKatrin Lamszus
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<div>Abstract<p><b>Purpose:</b> Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltrating T cells (tumor-infiltrating lymphocytes; TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion.</p><p><b>Experimental Design:</b> We used flow cytometry and cytokine assays to profile TILs and peripheral blood lymphocytes (PBLs) from patients with GBM, comparing newly diagnosed or recurrent GBM to long-term survivors (LTS) and healthy donors. TCR sequencing was performed on paired samples of newly diagnosed and recurrent GBM.</p><p><b>Results:</b> We identified a clear immune signature of exhaustion and clonal restriction in the TILs of patients with GBM. Exhaustion of CD8<sup>+</sup> TILs was defined by an increased prevalence of PD-1<sup>+</sup>, CD39<sup>+</sup>, Tim-3<sup>+</sup>, CD45RO<sup>+</sup>, HLA-DR<sup>+</sup> marker expression, and exhibition of an effector-/transitional memory differentiation phenotype, whereas KLRG1 and CD57 were underrepresented. Immune signatures were similar in primary and recurrent tumors; however, restricted TCR repertoire clonality and a more activated memory phenotype were observed in TILs from recurrent tumors. Moreover, a reduced cytokine response to PHA stimulation in the blood compartment indicates a dysfunctional peripheral T-cell response in patients with GBM. LTS displayed a distinct profile, with abundant naïve and less exhausted CD8<sup>+</sup> T cells.</p><p><b>Conclusions:</b> TILs and PBLs exhibit contrasting immune profiles, with a distinct exhaustion signature present in TILs. While the exhaustion profiles of primary and recurrent GBM are comparable, TCR sequencing demonstrated a contracted repertoire in recurrent GBM, concomitant with an increased frequency of activated memory T cells in recurrent tumors. <i>Clin Cancer Res; 24(17); 4187–200. ©2018 AACR</i>.</p><p><i>See related commentary by Jackson and Lim, p. 4059</i></p></div>Keywords:
Tumor-infiltrating lymphocytes
Immunophenotyping
Immunophenotyping
Tumor-infiltrating lymphocytes
Cytometry
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BCG vaccine is one of the most commonly-administered vaccines worldwide. Studies suggest the protective efficacy of BCG against TB is better for children than for adults. One potential explanation is that BCG induces a better protective immune response in children. Twenty six children and adults were immunised with BCG. The proportion of Th1-cytokine-producing mycobacterial-specific T cells, and the concentrations of secreted cytokines, were measured before and 10 weeks after BCG immunisation. A significant increase in the proportion of mycobacterial-specific cytokine-producing T cells was observed in both age groups. After BCG immunisation, children and adults had comparable proportions of mycobacterial-specific polyfunctional CD4 T cells when measured relative to the total number of CD4 T cells. However, relative to the subset of Th-1-cytokine-producing CD4 T cells, the proportion of polyfunctional cells was greater in children. Concentrations of secreted cytokines were comparable in children and adults. These findings suggest that the mycobacterial-specific cell-mediated immune response induced by BCG immunisation in children and adults is similar. The implication of a shift to a more polyfunctional immune response within the Th1-cytokine-producing CD4 T cells in children is uncertain as this aspect of the immune response has not been assessed as a potential correlate of protection against TB.
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AbstractHIV infection is associated with both a hyperactivity of the immune system and decreased immune responses against specific antigens. A similar pattern is observed when considering cytokine production in HIV-infected patients. Several cytokines are spontaneously produced at an increased level, whereas other cytokines playing an important role during cell-mediated immune responses are produced at a low level following stimulation. This deregulation of cytokine production may participate to the immune deficiency, both by impairing immune responses and by accelerating CD4+ T lymphocyte destruction. Chemokine receptors have recently been shown to function as coreceptors for the virus, and to govern its cellular tropism. Heterogeneous expression of chemokine receptor may contribute to differences in infectability as well as in rate of progression of the disease between individuals. Better understanding of the role of cytokines and chemokines in HIV infection suggests new therapeutic approaches where administration of cytokines or cytokine antagonists may allow the immune system to function in better conditions, to stimulate antiviral and antiinfectious immune defenses, and to limit viral spread.Key Words: HIVCytokinesChemokines
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HIV infection is associated with both a hyperactivity of the immune system and decreased immune responses against specific antigens. A similar pattern is observed when considering cytokine production in HIV-infected patients. Several cytokines are spontaneously produced at an increased level, whereas other cytokines, playing an important role during cell-mediated immune responses, are produced at a low level following stimulation. This deregulation of cytokine production may participate in the immune deficiency, both by impairing immune responses and by accelerating CD4+ T-lymphocyte destruction. In addition to contributing to the immune disequilibrium of the disease, impaired cytokine production in HIV-infected patients may contribute to the emergence and to the clinical symptoms of several complications of the disease, such as opportunistic infections, Kaposi's sarcoma and lymphomas. Better understanding of the role of cytokines in HIV infection may suggest new therapeutic approaches in which administration of cytokines or cytokine antagonists may allow the immune system to function more effectively and may stimulate antiviral and anti-infectious immune defences.
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Cytokines are important soluble signalling molecules that dictate and coordinate inflammatory and immune responses. Further understanding the role of cytokines in the pathobiologic mechanisms of pulmonary inflammatory and immune diseases holds the key to the development of effective prophylactic and therapeutic strategies. In the last several years, the use of models of human pulmonary diseases established either in normal adult animals, mice deficient for a given immune cell type or cytokine, or mice engineered to overexpress a given cytokine, has remarkably facilitated our understanding of the mechanisms operating in human disease. Cytokines that are involved in pulmonary inflammatory and immune conditions may be generally divided into groups of pro-inflammatory, anti-inflammatory and growth-stimulatory cytokines. While pro-inflammatory cytokines can be detrimental under such severe conditions as endotoxemia and fibrosis, they are required in host resistance against infectious agents. Anti-inflammatory cytokines play an important role in controlling the extent of tissue inflammatory/immune responses. Overexpression of growth-stimulatory cytokines are often directly associated with tissue fibrotic responses. In this review, the findings attained from experimental models by us and others were discussed with emphasis on cellular and histopathologic alterations, cytokine-mediated molecular mechanisms and the prospects of cytokine-based therapeutic strategies. Due to the restrict space, we chose to focus only on models for endotoxic lung, endotoxemia, acute pulmonary infections by extracellular Gram-negative bacteria, chronic pulmonary infections by intracellular myco-bacteria, allergic airways inflammation and pulmonary fibrosis.
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In article presented results of the study of basic levels of regulatory cytokines in patients with various forms of Epstein-Barr virus (EBV) infection. Analysis of the dynamics of cytokine profile in patients with EBV infection revealed the opposite changes studied synthesis of proinflammatory and anti-inflammatory cytokines, which was the basis for the establishment of the four types of immune response. The findings confirm the existence of cytokine imbalance with EBV infection. The established types of immune responses indicate inadequate cell humoral reactivity in a long persistence of EBV, which manifests a tendency to suppression of cell-mediated and humoral immune response enhancement mechanisms and displayed in the clinical and biochemical manifestations of the disease, and also leads to prolonged undulating course.
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textabstractThe human body has an extensive defence mechanism (immune system) for coping with pathogens. It is regulated by signalling molecules called cytokines. Cytokines are produced by various cells of the immune system such as leucocytes (e.g. T-cells and macrophages) but also by nasal and pulmonary epithelial tissue. There are several different types of cytokines. Th1 cytokines are involved in the eradication of bacterial and viral pathogens, while Th2 cytokines are involved in the defence against parasites. The production of Th1 cytokines is suppressed by Th2 cytokines and vice-versa so that the production of both cytokines is kept in balance. An overproduction of Th1 cytokines is found in auto-immune disorders, while allergic disease is frequently accompanied by high Th2 cytokine production. Furthermore, pro-inflammatory cytokines can induce general inflammatory reactions, while anti¬inflammatory and regulatory cytokines may downregulate these responses.
Immune responses in newborns are immature. This is seen in relatively high levels of Th2 and regulatory cytokines and low levels of Th1 cytokines compared to adults. The infant immune system matures with age. This maturation process consists of a relative increase in the production of Th1 cytokines compared to Th2 cytokines. Viral respiratory infections in infants may stimulate immune matura¬tion by their repeated Th1 stimulating effect, and thereby reduce the risk of a child developing Th2-mediated allergic disease. This hypothesis was first proposed by Professor Strachan in 1989 and is known as the ’hygiene hypothesis’.In the VI¬GALL study (VIGALL is the Dutch abbreviation for virally-mediated allergy), we examined whether respiratory infections predominantly induced by viruses may affect the maturation of the immune system and the development of allergic dis¬ease. We therefore looked to see which respiratory viruses are most prevalent in infants and what types of immune response are induced in the noses of these chil¬dren during infection and when healthy. We then examined whether the number of respiratory infections and the maturation of the immune system were related.
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In article presented results of the study of basic levels of regulatory cytokines in patients with various forms of Epstein-Barr virus infection. Analysis of the dynamics of cytokine profile in patients with Epstein-Barr virus infection revealed the opposite changes studied synthesis of proinflammatory and anti-inflammatory cytokines, which was the basis for the establishment of the four types of immune response. The findings confirm the existence of cytokine imbalance with Epstein-Barr virus infection. The established types of immune responses indicate inadequate cell humoral reactivity in a long persistence of Epstein-Barr virus infection, which manifests a tendency to suppression of cell-mediated and humoral immune response enhancement mechanisms and displayed in the clinical and biochemical manifestations of the disease, and also leads to prolonged undulating course. The results of studies confirm the existence of cytokine imbalance in various forms of EBV infection. The established types of immune response indicate inadequate cellular-humoral reactivity of the organism under the conditions of long-term EBV persistence. This is manifested by a tendency to suppress cell-mediated and increased humoral mechanisms of the immune response and is displayed in the clinical and biochemical manifestations of the disease and leads to a prolonged wave-like course of the disease. Interesting and promising are studies aimed at the medical correction of identified disorders in established types of immune response in patients with HEVE and studying the effects of the latter on the outcomes of the disease, the development of complications and activity of the process, which will be the subject of our further study.
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