Translocator protein (18kDA) (TSPO) marks mesenchymal glioblastoma cell populations characterized by elevated numbers of tumor-associated macrophages.

TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas.

Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy.

Tumor-derived extracellular vesicles (EVs) have been associated with immune evasion and tumor progression. We show that the RNA-sensing receptor RIG-I within tumor cells governs biogenesis and immunomodulatory function of EVs. Cancer-intrinsic RIG-I activation releases EVs, which mediate dendritic cell maturation and T cell antitumor immunity, synergizing with immune checkpoint blockade.

Changes in adenoviral chromatin organization precede early gene activation upon infection.

Within the virion, adenovirus DNA associates with the virus-encoded, protamine-like structural protein pVII. Whether this association is organized, and how genome packaging changes during infection and subsequent transcriptional activation is currently unclear. Here, we combined RNA-seq, MNase-seq, ChIP-seq, and single genome imaging during early adenovirus infection to unveil the structure- and time-resolved dynamics of viral chromatin changes as well as their correlation with gene transcription.

Targeting ACC1 in T cells ameliorates psoriatic skin inflammation.

Psoriasis is a chronic inflammatory skin disease driven by the IL-23/IL-17 axis. It results from excessive activation of effector T cells, including T helper (Th) and cytotoxic T (Tc) cells, and is associated with dysfunctional regulatory T cells (Tregs). Acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme of fatty acid synthesis (FAS), directs cell fate decisions between Th17 and Tregs and thus could be a promising therapeutic target for psoriasis treatment.

Immune profile of patients with peritoneal carcinomatosis selected for CRS-HIPEC therapy.

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal carcinomatosis (PC) from colorectal cancer (CRC), which is otherwise a terminal stage of disease. Nevertheless, survival outcomes are only marginally superior to other treatments. This fact highlights the need for better strategies to control intra-abdominal disease recurrence after CRS-HIPEC, including the complementary use of immunotherapies.

Inflammatory Cues Direct Skin-Resident Type 1 Innate Lymphoid Cells to Adopt a Psoriasis-Promoting Identity.

Innate lymphoid cells (ILCs) are gatekeepers in barrier organs, where they maintain tissue integrity and contribute to host defense as well as tissue repair. Inappropriate activation of ILCs, however, can lead to immunopathology with detrimental results. In this study, we focused on type 1 ILCs (ILC1s), which under inflammatory conditions constitute a poorly defined population with ambiguous functions.

Scaffold-Based (Matrigel™) 3D Culture Technique of Glioblastoma Recovers a Patient-like Immunosuppressive Phenotype.

Conventional 2D cultures are commonly used in cancer research though they come with limitations such as the lack of microenvironment or reduced cell heterogeneity. In this study, we investigated in what respect a scaffold-based (Matrigel™) 3D culture technique can ameliorate the limitations of 2D cultures. NGS-based bulk and single-cell sequencing of matched pairs of 2D and 3D models showed an altered transcription of key immune regulatory genes in around 36% of 3D models, indicating the reoccurrence of an immune suppressive phenotype.

CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process.

To enhance the potency of chimeric antigen receptor (CAR) engineered T cells in solid cancers, we designed a novel cell-based combination strategy with an additional therapeutic mode of action. CAR T cells are used as micropharmacies to produce a targeted pro-coagulatory fusion protein, truncated tissue factor (tTF)-NGR, which exerts pro-coagulatory activity and hypoxia upon relocalization to the vascular endothelial cells that invade tumor tissues. Delivery by CAR T cells aimed to induce locoregional tumor vascular infarction for combined immune-mediated and hypoxic tumor cell death.

Analysis of long-term mortality after total body irradiation-based and melphalan-based chemotherapy conditioning for acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for selected patients with acute myeloid leukemia. Yet, the influence of total body irradiation (TBI)-based conditioning as compared to non-TBI-based conditioning on long-term mortality is unclear. We retrospectively evaluated outcomes after TBI-based (n = 91) and non-TBI-based conditioning (melphalan-based, n = 248) for 1st allo-HSCT patients transplanted at the University Hospital Regensburg between 1999 and 2020.

IRF4 downregulation improves sensitivity and endurance of CAR T cell functional capacities.

Chimeric antigen receptor (CAR) modified T cells can induce complete remissions in patients with advanced hematological malignancies. Nevertheless, the efficacy is mostly transient and remains so far poor in the treatment of solid tumors. Crucial barriers to long-term CAR T cell success encompass loss of functional capacities known as "exhaustion", among others.

Intestinal IgA-positive plasma cells are highly sensitive indicators of alloreaction early after allogeneic transplantation and associate with both graft-versus-host disease and relapse-related mortality.

Intestinal immunoglobulin A (IgA) is strongly involved in microbiota homeostasis. Since microbiota disruption is a major risk factor of acute graft-versus-host disease (GvHD), we addressed the kinetics of intestinal IgA-positive (IgA+) plasma cells by immunohistology in a series of 430 intestinal biopsies obtained at a median of 1,5 months after allogeneic stem cell transplantation (allo-SCT) from 115 patients (pts) at our center. IgA+ plasma cells were located in the subepithelial lamina propria and suppressed in the presence of histological aGvHD (GvHD Lerner stage 0: 131+/-8 IgA+ plasma cells/mm2; stage 1-2: 108+/-8 IgA+ plasma cells/mm2; stage 3-4: 89+/-16 IgA+ plasma cells/mm2; P=0.

Innate immunity and early liver inflammation.

The innate system constitutes a first-line defence mechanism against pathogens. 80% of the blood supply entering the human liver arrives from the splanchnic circulation through the portal vein, so it is constantly exposed to immunologically active substances and pathogens from the gastrointestinal tract. Rapid neutralization of pathogens and toxins is an essential function of the liver, but so too is avoidance of harmful and unnecessary immune reactions.

Engineered Treg cells as putative therapeutics against inflammatory diseases and beyond.

Regulatory T (Treg) cells ensure tolerance against self-antigens, limit excessive inflammation, and support tissue repair processes. Therefore, Treg cells are currently attractive candidates for the treatment of certain inflammatory diseases, autoimmune disorders, or transplant rejection. Early clinical trials have proved the safety and efficacy of certain Treg cell therapies in inflammatory diseases.

Autocrine activation of MAPK signaling mediates intrinsic tolerance to androgen deprivation in LY6D prostate cancer cells.

The emergence of castration-resistant prostate cancer remains an area of unmet clinical need. We recently identified a subpopulation of normal prostate progenitor cells, characterized by an intrinsic resistance to androgen deprivation and expression of LY6D. We here demonstrate that conditional deletion of PTEN in the murine prostate epithelium causes an expansion of transformed LY6D progenitor cells without impairing stem cell properties.

CAR and TCR form individual signaling synapses and do not cross-activate, however, can co-operate in T cell activation.

In engineered T cells the CAR is co-expressed along with the physiological TCR/CD3 complex, both utilizing the same downstream signaling machinery for T cell activation. It is unresolved whether CAR-mediated T cell activation depends on the presence of the TCR and whether CAR and TCR mutually cross-activate upon engaging their respective antigen. Here we demonstrate that the CD3ζ CAR level was independent of the TCR associated CD3ζ and could not replace CD3ζ to rescue the TCR complex in CD3ζ KO T cells.

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.

Introduction: The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment.

A20 as a Potential New Tool in Predicting Recurrence and Patient's Survival in Oral Squamous Cell Carcinoma.

A20, known as a potent inhibitor of NF-κB signaling, has been characterized in numerous clinical as well as preclinical studies. Recently, especially in various malignant diseases, the prognostic and therapeutic relevance of A20 was investigated. In oral squamous cell carcinoma (OSCC) however, the characterization of A20 is uncharted territory.

Tumor gene signatures that correlate with release of extracellular vesicles shape the immune landscape in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) evade immune responses through multiple resistance mechanisms. Extracellular vesicles (EVs) released by the tumor and interacting with immune cells induce immune dysfunction and contribute to tumor progression. This study evaluates the clinical relevance and impact on anti-tumor immune responses of gene signatures expressed in HNSCC and associated with EV production/release.

Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment.

Introduction: Glutamine deficiency is a well-known feature of the tumor environment. Here we analyzed the impact of glutamine deprivation on human myeloid cell survival and function.

Methods: Different types of myeloid cells were cultured in the absence or presence of glutamine and/or with L-methionine-S-sulfoximine (MSO), an irreversible glutamine synthetase (GS) inhibitor.

Murine cytomegalovirus reactivation concomitant with acute graft-versus-host disease is controlled by antibodies.

Reactivation of human cytomegalovirus (HCMV) from latency is a frequent complication following hematopoietic stem cell transplantation (HSCT). The development of acute graft-versus-host disease (GVHD) is a significant risk factor for HCMV disease. Using a murine GVHD model in animals latently infected with murine CMV (MCMV), we studied preventive and therapeutic interventions in this high-risk scenario of HSCT.

CAR T cell therapy becomes CHIC: "cytokine help intensified CAR" T cells.

Chimeric antigen receptors (CARs) in the canonical "second generation" format provide two signals for inducing T cell effector functions; the primary "signal-1" is provided through the TCR CD3ζ chain and the "signal-2" through a linked costimulatory domain to augment activation. While therapy with second generation CAR T cells can induce remissions of leukemia/lymphoma in a spectacular fashion, CAR T cell persistence is frequently limited which is thought to be due to timely limited activation. Following the "three-signal" dogma for inducing a sustained T cell response, cytokines were supplemented to provide "signal-3" to CAR T cells.

A CD19-Anti-ErbB2 scFv Engager Protein Enables CD19-Specific CAR T Cells to Eradicate ErbB2 Solid Cancer.

The efficacy of CD19-specific CAR T cells in the treatment of leukemia/lymphoma relies, at least in part, on the unique properties of the particular CAR and the presence of healthy B cells that enhance the target cell lysis and cytokine secretion through repetitive stimulation. Here, we report to apply the same CAR to target solid tumors, such as ErbB2 carcinoma. CD19 CAR T cells are redirected towards the ErbB2 cells by a fusion protein that is composed of the herceptin-derived anti-ErbB2 scFv 4D5 linked to the CD19 exodomain.

Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8 T cells.

Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8 TIL states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis.