Wolfram Hoetzenecker

Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth

Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.

ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression

Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2–related factor 2 (NRF2)–dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3−/− mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3−/− mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3−/−Il6−/− mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3−/− mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.

Interleukin 23 Expression in Pyoderma Gangrenosum and Targeted Therapy With Ustekinumab

BACKGROUND Interleukin (IL)-23 is involved in the pathogenesis of the chronic inflammatory Crohn disease. Pyoderma gangrenosum (PG) is often associated with and can even be the first manifestation of this disease and has abundant neutrophilic infiltration. Because IL-23 plays a critical role in driving inflammation associated with IL-17 production and especially neutrophil recruitment, we suspect that PG might be driven by a pathogenetic mechanism similar to that of inflammatory bowel diseases or psoriasis. OBSERVATIONS Tissue sample analysis showed highly elevated expression of IL-23 on both transcriptional and protein level in a recalcitrant PG lesion. On the basis on these data, a treatment targeting the p40 subunit of the heterodimeric IL-23 with the monoclonal antibody ustekinumab was started. Therapy with ustekinumab resulted in a significant decrease of IL-23 expression in PG and healing after 14 weeks of treatment. No relapse occurred in a 6-month follow-up period. CONCLUSIONS Our data provide evidence of an IL-23-dominated inflammatory infiltrate in PG. This might specify a new concept for PG pathophysiology and suggests a possibility for using ustekinumab as a therapeutic agent in this disease.

IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells.

Significance Interleukin 4 (IL-4) has been shown to be highly protective against delayed type hypersensitivity and organ-specific autoimmune and autoinflammatory reactions in mice and humans, but its mode of action has remained controversial and has failed to be explained solely by redirection of TH1/TH17 toward a TH2-type immune response. Here we uncovered that IL-4 selectively suppresses IL-23 transcription and secretion by cells of the innate immune system. We further describe a previously unidentified therapeutic mode of action of IL-4 in TH17-mediated inflammation, and a physiologically highly relevant approach to selectively target IL-23/TH17-dependent inflammation while sparing IL-12 and TH1 immune responses. Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-γ–producing TH1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12–producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4–mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6- and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/TH17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/TH17 responses without blocking IL-12/TH1, selective IL-4–mediated IL-23/TH17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12–dependent TH1 responses.

Atrial septal defect repair after a 10-month treatment with bosentan in a patient with severe pulmonary arterial hypertension: A case report

Congenital type II atrial septal defect (ASD) is associated with precapillary pulmonary hypertension (PAH) in roughly 10% of cases. Principally, closure of the shunt lesion is recommended, and large ASDs must be repaired in early childhood to prevent Eisenmenger’s syndrome. Once severe pulmonary hypertension or Eisenmenger’s syndrome has developed, ASD closure is problematic due the increased risk of right ventricular failure and pulmonary hypertensive crisis. At this stage, heart–lung transplantation is the only surgical option. Nonsurgical strategies include supplemental oxygen, digitalis, anticoagulation, and vasodilator treatments. In contrast to the traditional rule of inoperability of an ASD with severe pulmonary hypertension, single case reports have demonstrated that surgical correction of an ASD is feasible but requires longtime preand postoperative treatment with vasodilators. Endothelin receptor antagonists are a new class of vasoactive substances, some of which (eg, bosentan) are orally active. Bosentan has been shown to lower pulmonary artery pressure (PAP) and to induce reverse remodeling of the pulmonary arteries. We report the case of a patient with type II ASD and severe pulmonary hypertension. Successful surgical closure of the ASD was possible with near-normalized PAPs after 10 months of ‘‘conditioning’’ medication with bosentan.

Brentuximab as a treatment for CD30+ mycosis fungoides and Sézary syndrome.

IMPORTANCE The prognosis of advanced cutaneous T-cell lymphoma (CTCL), including Sézary syndrome and mycosis fungoides (MF), is poor. So far, no curative option apart from allogeneic stem cell transplantation is available. Large cell transformation often hallmarks cases with a more aggressive clinical course, and large tumor cells may express CD30. Recently, brentuximab vedotin, a conjugate of an anti-CD30 antibody and monomethylauristatin E, which inhibits the polymerization of microtubuli, has produced promising results in phase 2 trials in CD30+ Hodgkin lymphoma and anaplastic large cell lymphoma. OBSERVATIONS We describe 4 patients with advanced CTCL, 3 with MF and 1 with Sézary syndrome, who were treated with brentuximab. All patients had received multiple previous systemic therapies. In 2 cases of MF, a remission enabling subsequent allogeneic stem cell transplantation was achieved. CONCLUSIONS AND RELEVANCE Brentuximab is a well-tolerated, promising new treatment option for advanced CTCL that can be integrated in an allogeneic stem cell transplantation plan by selectively depleting malignant CD30+ cutaneous lymphoma cells.

Mononuclear cell secretome protects from experimental autoimmune myocarditis

Abstract Aims Supernatants of serum-free cultured mononuclear cells (MNC) contain a mix of immunomodulating factors (secretome), which have been shown to attenuate detrimental inflammatory responses following myocardial ischaemia. Inflammatory dilated cardiomyopathy (iDCM) is a common cause of heart failure in young patients. Experimental autoimmune myocarditis (EAM) is a CD4+ T cell-dependent model, which mirrors important pathogenic aspects of iDCM. The aim of this study was to determine the influence of MNC secretome on myocardial inflammation in the EAM model. Methods and results BALB/c mice were immunized twice with an alpha myosin heavy chain peptide together with Complete Freund adjuvant. Supernatants from mouse mononuclear cells were collected, dialysed, and injected i.p. at Day 0, Day 7, or Day 14, respectively. Myocarditis severity, T cell responses, and autoantibody formation were assessed at Day 21. The impact of MNC secretome on CD4+ T cell function and viability was evaluated using in vitro proliferation and cell viability assays. A single high-dose application of MNC secretome, injected at Day 14 after the first immunization, effectively attenuated myocardial inflammation. Mechanistically, MNC secretome induced caspase-8-dependent apoptosis in autoreactive CD4+ T cells. Conclusion MNC secretome abrogated myocardial inflammation in a CD4+ T cell-dependent animal model of autoimmune myocarditis. This anti-inflammatory effect of MNC secretome suggests a novel and simple potential treatment concept for inflammatory heart diseases.

Consequences of a Wait-and-See Strategy for Benign Metastasizing Leiomyomatosis of the Lung

Pulmonary benign metastasizing leiomyomatosis (BML) is a rare smooth-muscle cell disorder of the lung. Most BML lesions stay constant in size for a long time. The prevailing treatment option is primary excision of the nodules or if unresectable, long-time hormone therapy. Herein, we present a case of BML in which a wait-and-see strategy after diagnosis was decided. Fourteen years later a routine chest roentgenogram revealed multiple bi-lobar BML lesions with a giant cyst filling the whole left lung cavity. We conclude that a wait-and-see procedure for BML is feasible, but primary resection of the BML tumor masses is preferable to avoid complications as described in our case.

The Role of Malassezia spp. in Atopic Dermatitis

Malassezia spp. is a genus of lipophilic yeasts and comprises the most common fungi on healthy human skin. Despite its role as a commensal on healthy human skin, Malassezia spp. is attributed a pathogenic role in atopic dermatitis. The mechanisms by which Malassezia spp. may contribute to the pathogenesis of atopic dermatitis are not fully understood. Here, we review the latest findings on the pathogenetic role of Malassezia spp. in atopic dermatitis (AD). For example, Malassezia spp. produces a variety of immunogenic proteins that elicit the production of specific IgE antibodies and may induce the release of pro-inflammatory cytokines. In addition, Malassezia spp. induces auto-reactive T cells that cross-react between fungal proteins and their human counterparts. These mechanisms contribute to skin inflammation in atopic dermatitis and therefore influence the course of this disorder. Finally, we discuss the possible benefit of an anti-Malassezia spp. treatment in patients with atopic dermatitis.

Novel therapies for cutaneous T-cell lymphoma: what does the future hold?

Introduction: Cutaneous T-cell lymphomas (CTCLs) represent a group of extranodal non-Hodgkin lymphomas, of which mycosis fungoides (MF) is the most frequent. Standard therapeutic approaches are well established and often achieve stable disease. However, cure for MF is rare and thus novel therapies are needed. Areas covered: This review provides a discussion of the most promising new therapeutic approaches in the management of MF and other rare CTCLs. It includes targeted therapies with antibodies against surface molecules on malignant T cells (e.g., brentuximab), novel chemotherapeutic agents (e.g., pralatrexate), small-molecule compounds (e.g., panobinostat) and evidence of emerging targets in CTCLs (e.g., anti-IL-31). It also provides discussion of immune checkpoint inhibitors such as anti-PD1 that are worth considering in the treatment of leukaemic CTCL variants. Finally, it gives a brief overview of the possible use of stem-cell transplantation. Expert opinion: There is no doubt that progress has been made in the treatment of CTCLs with new, innovative and promising therapies approaching. However, there is still an urgent need to identify and test additional targets in well-designed clinical trials.