Human γδ T lymphocytes for immunotherapeutic strategies against cancer

γδ T lymphocytes are a numerically small subset of T cells with potent cytotoxic activity against a variety of tumor cells. Human γδ T cells expressing the Vγ9Vδ2 T cell antigen receptor recognize endogenous pyrophosphate molecules that are overproduced in transformed cells. Moreover, the intracellular accumulation of such pyrophosphates is strongly enhanced by aminobisphosphonates used in the treatment of osteoporosis and bone metastasis in certain cancer patients. A new concept of cancer immunotherapy is based on the endogenous activation of γδ T cells with aminobisphosphonates plus low-dose interleukin-2

Editorial: "Recent Advances in Gamma/Delta T Cell Biology: New Ligands, New Functions, and New Translational Perspectives"

Since their discovery in the mid-1980s, interest in the immunological significance of γδ T cells has been subject to oscillations. The initial excitement over the unexpected discovery of a second T cell receptor (TCR) was followed by years of uncertainty as to the biological importance of these ambivalent T cells. Major breakthroughs led to the identification of specific and unique antigens for the γδ TCR and accumulating evidence now shows that γδ T cells play a major role in local immunosurveillance, thereby controlling tumorigenesis. Since 2004, biannual international γδ T cell conferences are held to bring together experts in basic and clinical γδ T cell research. To make accessible and synthesize the body of knowledge that has been put together, to date, we have organized a “Research Topic” on γδ T cells consisting of a collection of original articles and focused reviews written by leading experts in the field. The idea of this Research Focus was to present the current status and “hot topics” as well as clinical perspectives on γδ T cell research

Editorial: Next generation γδ T cell-based tumor immunotherapy

The discovery of the gd T-cell receptor (TCR) and its ability to confer potent cytotoxic activity in CD3+ cells some 35 years ago sparked the initial proliferation in research that garnered widespread interest in the biology and function of gd T cells

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System

Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.Peer reviewe

Vitamin C, From Supplement to Treatment: A Re-Emerging Adjunct for Cancer Immunotherapy?

Vitamin C (VitC), in addition to its role as a general antioxidant, has long been considered to possess direct anti-cancer activity at high doses. VitC acts through oxidant and epigenetic mechanisms, which at high doses can exert direct killing of tumor cells in vitro and delay tumor growth in vivo. Recently, it has also been shown that pharmacologic-dose VitC can contribute to control of tumors by modulating the immune system, and studies have been done interrogating the role of physiologic-dose VitC on novel adoptive cellular therapies (ACTs). In this review, we discuss the effects of VitC on anti-tumor immune cells, as well as the mechanisms underlying those effects. We address important unanswered questions concerning both VitC and ACTs, and outline challenges and opportunities facing the use of VitC in the clinical setting as an adjunct to immune-based anti-cancer therapies

Monocyte-dependent co-stimulation of cytokine induction in human γδ T cells by TLR8 RNA ligands

Human Vγ9Vδ2 T cells recognize pyrophosphates produced by microbes and transformed cells and play a role in anti-infective immunity and tumor surveillance. Toll-like receptors (TLR) are pattern recognition receptors in innate immune cells which sense microbial structures including nucleic acids. Given that γδ T cells are in clinical development for application in cellular cancer immunotherapy and TLR ligands have potent adjuvant activity, we investigated the co-stimulatory role of selected TLR ligands in γδ T-cell activation. Here we have used recently described RNA ligands for TLR7 and TLR8 together with Vγ9Vδ2 T-cell specific pyrophosphate antigens to analyze the rapid cytokine induction in Vδ2 T cells as well as the accessory cell requirements. While TLR8- as well as TLR7/8-specific RNA did not induce IFN-γ in Vδ2 T cells on their own, they provided strong co-stimulation for Vδ2 T cells within peripheral blood mononuclear cells in the presence of additional T-cell receptor activation. In contrast, TLR7 ligands were ineffective. Purified γδ T cells did not directly respond to TLR8 co-stimulation but required the presence of monocytes. Further experiments revealed a critical role of IL-1β and IL-18, and to a slightly lesser extent of IL-12p70, in the co-stimulation of Vδ2 T cells by TLR8 and TLR7/8 RNA ligands. Results of intracellular cytokine expression were validated by ELISA analysis of cytokines in cell culture supernatants. The cell context-dependent adjuvant activity of TLR8 and TLR7/8 RNA ligands described here might be important for the future optimization of γδ T-cell based cancer immunotherapy

Total Immunoglobulin Y Detection in Avian Malaria-infected Domestic Birds from Uganda

Background and Aim: The use of microscopy-based and polymerase chain reaction (PCR)-based methods have offered considerable insights in detecting avian blood malaria infection in domestic and wild birds. The infection has a significant impact on the immunity of birds. However, some observations concerning the role of immune system in controlling the infection continue to question the extent of immune factors involved. To address this, the current study hypothesized that avian malaria infection may influence the humoral response of domestic birds. Materials and Methods: The prevalence of avian malaria parasites (both Plasmodium and Haemoproteus spp.) in free-ranging domestic birds from Uganda was evaluated using PCR and the level of Immunoglobulin Y (IgY) antibody in malaria-infected and uninfected birds was determined using enzyme-linked immunosorbent assay (ELISA). Result: The results showed that 10 (15.15%) of 66 individually tested birds were infected with avian malaria parasites. Interestingly, an increase in the level of IgY associated with the infection was found. Of note, the uninfected birds exhibited a consistent level of IgY, however, less than in malaria-positive birds. It is likely that avian malaria-independent factors may have been involved in this induction in uninfected birds. Conclusion: The data obtained in this study suggest that avian malaria infections influence the production of IgY in domestic birds, therefore indicating the potential of IgY as an immune biomarker for screening avian malaria infection in domestic birds. However, these observations are subject to further investigation with larger sample size.Rufford Small Grants (RSG

Monitoring Circulating γδ T Cells in Cancer Patients to Optimize γδ T Cell-Based Immunotherapy

The success of γδ T cell-based immunotherapy, where the cytotoxic activity of circulating γδ T lymphocytes is activated by nitrogen-containing bisphosphonates (n-BP), or possibly by bispecific antibodies or the combination of both, requires a profound knowledge of patients' γδ T cells. A possible influence of radio- or chemotherapy on γδ T cells as well as their reported exhaustion after repetitive treatment with n-BP or their lack of response to various cancers can be easily determined by the monitoring assays described in this perspective article. Monitoring the absolute cell numbers of circulating γδ T cell subpopulations in small volumes of whole blood from cancer patients and determining γδ T cell cytotoxicity using the Real-Time Cell Analyzer can give a more comprehensive assessment of a personalized tumor treatment. Possible future directions such as the combined usage of n-BP or phosphorylated antigens together with bispecific antibodies that selectively target γδ T cells to tumor-associated antigens, will be discussed. Such strategies induce expansion and enhance γδ T cell cytotoxicity and might possibly avoid their exhaustion and overcome the immunosuppressive tumor microenvironment

Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells

The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9aclow and inducible H3K9achigh expression in Vδ2 T cells. The detailed analysis of H3K9aclow Vδ2 T cells revealed a significant reversion of TEMRA to TEM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer

Hematopoietic stem cell involvement in BCR-ABL1-positive ALL as a potential mechanism of resistance to blinatumomab therapy

The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19 antigen on leukemic cells, which has been established as a novel mechanism to escape CD19-specific immunotherapies. Here, we provide evidence that CD19-negative (CD19–) relapse after CD19-directed therapy in BCP-ALL may be a result of the selection of preexisting CD19– malignant progenitor cells. We present 2 BCR-ABL1 fusion–positive BCP-ALL patients with CD19– myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1 positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. By using the same approach with 25 additional diagnostic samples from patients with BCR-ABL1–positive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major BCR-ABL1 transcript encoding P210BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190BCR-ABL1, only the CD19+ leukemia compartments were BCR-ABL1 positive (P = .02). Our data are of clinical importance, because they indicate that both CD19+ cells and CD19– precursors should be targeted to avoid CD19– relapses in patients with BCR-ABL1–positive ALL