Vdelta1 T cells are more resistant than Vdelta2 T cells to the immunosuppressive properties of galectin-3.

Ovarian carcinomas have the highest lethality amongst gynecological tumors. A problem after primary resection is the recurrence of epithelial ovarian carcinomas which is often associated with chemotherapy resistance. To improve the clinical outcome, it is of high interest to consider alternative therapy strategies.

Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic T1 cell responses in Crohn's disease.

Aberrant CD4 T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4 T cell reactions in patients with Crohn's disease (CD).

Tumor cell lysis and synergistically enhanced antibody-dependent cell-mediated cytotoxicity by NKG2D engagement with a bispecific immunoligand targeting the HER2 antigen.

Natural killer group 2 member D (NKG2D) plays an important role in the regulation of natural killer (NK) cell cytotoxicity in cancer immune surveillance. With the aim of redirecting NK cell cytotoxicity against tumors, the NKG2D ligand UL-16 binding protein 2 (ULBP2) was fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2). The resulting bispecific immunoligand ULBP2:HER2-scFv triggered NK cell-mediated killing of HER2-positive breast cancer cells in an antigen-dependent manner and required concomitant interaction with NKG2D and HER2 as revealed in antigen blocking experiments.

Affinity Maturation of B7-H6 Translates into Enhanced NK Cell-Mediated Tumor Cell Lysis and Improved Proinflammatory Cytokine Release of Bispecific Immunoligands via NKp30 Engagement.

Activating NK cell receptors represent promising target structures to elicit potent antitumor immune responses. In this study, novel immunoligands were generated that bridge the activating NK cell receptor NKp30 on NK cells with epidermal growth factor receptor (EGFR) on tumor cells in a bispecific IgG-like format based on affinity-optimized versions of B7-H6 and the Fab arm derived from cetuximab. To enhance NKp30 binding, the solitary N-terminal IgV domain of B7-H6 (ΔB7-H6) was affinity matured by an evolutionary library approach combined with yeast surface display.

Tumor resistance mechanisms and their consequences on γδ T cell activation.

Human γδ T lymphocytes are predominated by two major subsets, defined by the variable domain of the δ chain. Both, Vδ1 and Vδ2 T cells infiltrate in tumors and have been implicated in cancer immunosurveillance. Since the localization and distribution of tumor-infiltrating γδ T cell subsets and their impact on survival of cancer patients are not completely defined, this review summarizes the current knowledge about this issue.

Galectin-3 Released by Pancreatic Ductal Adenocarcinoma Suppresses γδ T Cell Proliferation but Not Their Cytotoxicity.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment with a dense desmoplastic stroma. The expression of β-galactoside-binding protein galectin-3 is regarded as an intrinsic tumor escape mechanism for inhibition of tumor-infiltrating T cell function. In this study, we demonstrated that galectin-3 is expressed by PDAC and by γδ or αβ T cells but is only released in small amounts by either cell population.

Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant gastrointestinal disease. The enzyme indoleamine-2,3-dioxgenase (IDO) is often overexpressed in PDAC and its downstream metabolite kynurenine has been reported to inhibit T cell activation and proliferation. Since γδ T cells are of high interest for T cell-based immunotherapy against PDAC, we studied the impact of IDO and kynurenine on γδ T cell cytotoxicity against PDAC cells.

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T cells and γδ T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of γδ T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors.

Pitfalls in the characterization of circulating and tissue-resident human γδ T cells.

Dissection of the role and function of human γδ T cells and their heterogeneous subsets in cancer, inflammation, and auto-immune diseases is a growing and dynamic research field of increasing interest to the scientific community. Therefore, harmonization and standardization of techniques for the characterization of peripheral and tissue-resident γδ T cells is crucial to facilitate comparability between published and emerging research. The application of commercially available reagents to classify γδ T cells, in particular the combination of multiple Abs, is not always trouble-free, posing major demands on researchers entering this field.

Real-time cell analysis (RTCA) to measure killer cell activity against adherent tumor cells in vitro.

The enhancement of immune responses against tumor cells is a main focus of cancer immunotherapy. Immunotherapeutic approaches comprise a broad range of clinical applications including adjuvant therapies, check point inhibitors, cellular therapies, oncolytic viruses or targeted biologics such as bispecific antibodies. The usage of bispecific antibodies is one promising approach to enhance cytotoxicity and to selectively target effector cells to tumor-associated antigens.

In vitro expansion of Vγ9Vδ2 T cells for immunotherapy.

Vγ9Vδ2 T cells can exhibit potent anti-tumor activity and have gained much attention as an interesting tool for cancer immunotherapy by adoptive cell transfer. In this chapter, we explain the different approaches for the in vitro expansion of Vγ9Vδ2 T cells for their subsequent adoptive transfer and present a detailed protocol for the successful in vitro expansion at the laboratory scale. Finally, we discuss strategies for optimization and parameters necessary for the adaption to a clinical scale protocol.

Bispecific antibodies enhance tumor-infiltrating T cell cytotoxicity against autologous HER-2-expressing high-grade ovarian tumors.

Epithelial ovarian cancer displays the highest mortality of all gynecological tumors. A relapse of the disease even after successful surgical treatment is a significant problem. Resistance against the current platinum-based chemotherapeutic standard regime requires a detailed ex vivo immune profiling of tumor-infiltrating cells and the development of new therapeutic strategies.

TRAIL-Receptor 4 Modulates γδ T Cell-Cytotoxicity Toward Cancer Cells.

Acquired immune evasion is one of the mechanisms that contributes to the dismal prognosis of cancer. Recently, we observed that different γδ T cell subsets as well as CD8 αβ T cells infiltrate the pancreatic tissue. Interestingly, the abundance of γδ T cells was reported to have a positive prognostic impact on survival of cancer patients.

Regulatory Interactions Between Neutrophils, Tumor Cells and T Cells.

Apart from their activity in combating infections, neutrophils play an important role in regulating the tumor microenvironment. Neutrophils can directly kill (antibody-coated) cancer cells, and support other immune anti-tumoral strategies. On the other hand, neutrophils can also exert pro-tumorigenic activities the production of factors which promote cancer growth, angiogenesis and metastasis formation.

POLE Score: a comprehensive profiling of programmed death 1 ligand 1 expression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) being characterized by a pronounced stromal compartment is commonly diagnosed at an advanced stage limiting curative treatment options. Although therapeutical targeting of immune checkpoint regulators like programmed death 1 ligand 1 (PD-L1) represent a promising approach that substantially improved survival of several highly aggressive malignancies, convincing indicators for response prediction are still lacking for PDAC which might be attributed to the insufficient characterization of PD-L1 status. Therefore, we investigated PD-L1 expression by immunohistochemistry in a well characterized cohort of 59 PDAC and 18 peritumoral tissues.

Anti-CD3 Fab Fragments Enhance Tumor Killing by Human γδ T Cells Independent of Nck Recruitment to the γδ T Cell Antigen Receptor.

T lymphocytes expressing the γδ T cell receptor (γδ TCR) can recognize antigens expressed by tumor cells and subsequently kill these cells. γδ T cells are indeed used in cancer immunotherapy clinical trials. The anti-CD3ε antibody UCHT1 enhanced the tumor killing activity of human γδ T cells by an unknown molecular mechanism.

ADAM17 inhibition enhances platinum efficiency in ovarian cancer.

Chemotherapeutic resistance evolves in about 70 % of ovarian cancer patients and is a major cause of death in this tumor entity. Novel approaches to overcome these therapeutic limitations are therefore highly warranted. A disintegrin and metalloprotease 17 (ADAM17) is highly expressed in ovarian cancer and required for releasing epidermal growth factor receptor (EGFR) ligands like amphiregulin (AREG).

Influence of physical activity on the immune system in breast cancer patients during chemotherapy.

Purpose: Physical activity can impact the immune system in different ways, e.g. by alteration of the humoral and cellular immune response.

In-depth immunophenotyping of patients with glioblastoma multiforme: Impact of steroid treatment.

Despite aggressive treatment regimens based on surgery and radiochemotherapy, the prognosis of patients with grade IV glioblastoma multiforme (GBM) remains extremely poor, calling for alternative options such as immunotherapy. Immunological mechanisms including the Natural Killer Group 2 member D (NKG2D) receptor-ligand system play an important role in tumor immune surveillance and targeting the NKG2D system might be beneficial. However, before considering any kind of immunotherapy, a precise characterization of the immune system is important, particularly in GBM patients where conventional therapies with impact on the immune system are frequently co-administered.

A novel Fc-engineered human ICAM-1/CD54 antibody with potent anti-myeloma activity developed by cellular panning of phage display libraries.

To identify antibodies suitable for multiple myeloma (MM) immunotherapy, a cellular screening approach was developed using plasma cell lines JK-6L and INA-6 and human synthetic single-chain fragment variable (scFv) phage libraries. Isolated phage antibodies were screened for myeloma cell surface reactivity. Due to its binding characteristics, phage PIII-15 was selected to generate the scFv-Fc fusion protein TP15-Fc with an Fc domain optimized for FcγRIIIa binding.

Hematopoietic stem cell involvement in 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.

The Ambiguous Role of γδ T Lymphocytes in Antitumor Immunity.

γδ T cells play a role in immune surveillance because they recognize stress-induced surface molecules and metabolic intermediates that are frequently dysregulated in transformed cells. Hence, γδ T cells have attracted much interest as effector cells in cell-based immunotherapy. Recently, however, it has been realized that γδ T cells can also promote tumorigenesis through various mechanisms including regulatory activity and IL-17 production.