Dr. Haist is a clinician scientist who explores the tumor microenvironment of advanced skin cancer patients to identify predictive biomarkers and immunological signatures using single-cell multiplexing technologies. As a Ph.D. student, Dr. Haist investigated the role of tumor hypoxia and the adenosine system in patients with melanoma brain metastases treated with combined radiochemotherapy. Currently, Dr Haist is a Postdoctoral Fellow in Dr. Garry Nolan´s lab and comes with interest in multiplex technologies to analyze the organization of effective anti-tumor immune responses within the tumor microenvironment.
Honors & Awards
TRANSMED Jumpstart Fellowship, Else-Kröner Fresenius Foundation (2020)
Walter-Benjamin Fellowship, German Research Foundation (2022)
Staatsexamen, Johannes Gutenberg Universitat Mainz (2019)
Doctor of Medicine, Johannes Gutenberg Universitat Mainz (2021)
MD, Johannes-Gutenberg University Mainz, Germany and University of Zurich, Switzerland, Medicine (2019)
Dr. med., Department of Radiation Oncology and Radiotherapy, University Medical Center of the Johannes-Gutenberg University Mainz, Germany, Melanoma Immunotherapy (2021)
Garry Nolan, Postdoctoral Faculty Sponsor
Response to First-Line Treatment with Immune-Checkpoint Inhibitors in Patients with Advanced Cutaneous Squamous Cell Carcinoma: A Multicenter, Retrospective Analysis from the German ADOReg Registry.
2022; 14 (22)
Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.
View details for DOI 10.3390/cancers14225543
View details for PubMedID 36428636
Impaired regulatory T cell-dendritic cell interactions contribute to autoimmunity in leukocyte adhesion deficiency type-1.
Leukocyte Adhesion Deficiency Type-1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common beta-chain of the SS2 integrin family (CD18). The most prominent clinical symptoms are profound leukocytosis and high susceptibility to infections. At the same time, LAD-1 patients are prone to develop autoimmune diseases, but the molecular and cellular mechanisms that result in coexisting immunodeficiency and autoimmunity are still unresolved. CD4+FOXP3+ regulatory T cells (Treg) are known for their essential role in preventing autoimmunity. To understand the role of Treg in LAD-1 development and manifestation of autoimmunity we generated mice specifically lacking CD18 on Treg (CD18Foxp3), resulting in defective LFA-1 expression. Here we demonstrate a crucial role of LFA-1 on Treg to maintain immune homeostasis by modifying T cell - dendritic cell (DC) interactions and CD4+ T cell activation. Treg-specific CD18 deletion did not impair Treg migration into extra-lymphatic organs but resulted in shorter interactions of Treg with DC. In vivo, CD18Foxp3 mice developed spontaneous hyperplasia in lymphatic organs, and diffuse inflammation of the skin and in multiple internal organs. Thus, LFA-1 on Treg is required for the maintenance of immune homeostasis.
View details for DOI 10.1172/jci.insight.162580
View details for PubMedID 36346673
The Role of the Immune Phenotype in Tumor Progression and Prognosis of Patients with Mycosis Fungoides: A Quantitative Immunohistology Whole Slide Approach
2022; 11 (22)
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphomas, characterized by mature, skin-tropic CD4+ T-helper cells. In order to study the immune tumor microenvironment in MF patients, we performed immunohistochemical stains on MF biopsies, digitized whole-slide tissue sections, and performed quantitative analysis of the different immune cell subsets to correlate tissue parameters with the clinical data of patients, such as progression-free survival or overall survival.Overall, 35 patients who were treated between 2009 and 2019 and for whom one or more paraffin tissue blocks were available have been included in the present study (58 tissue specimens in total). Conventional immunohistochemistry stains for CD3, CD4, CD8, CD20 and CD30 were used for the analysis of the immune phenotype, and quantitative analysis was performed using QuPath as a quantitative digital pathology tool for bioimage analysis of whole slides.Analysis of tissue parameters for prognostic significance revealed that patients with a stronger infiltration by CD8+ lymphocytes within the tumor cell compartment had a higher risk of disease progression (p = 0.031) and showed a shorter progress-free survival (p = 0.038). Furthermore, a significant association of the percentage of CD30+ cells (median: 7.8%) with the risk of disease progression (p = 0.023) and progression-free survival (p = 0.023) was found. In relation to the clinical features of our patient cohort, a higher risk of disease progression (p = 0.015) and a shorter progression-free survival (p = 0.032) for older patients (>61 years) were observed.Our results demonstrated the prognostic relevance of large-cell transformation in mycosis fungoides and its strong association with the presence of CD30+ lymphocytes. Unlike previous reports, our study suggests an adverse prognostic role for CD8+ T cells in patients with mycosis fungoides. Moreover, our data indicate that the immune phenotype within the tumor microenvironment shows strong temporal heterogeneity and is altered in the course of tumor progression.
View details for DOI 10.3390/cells11223570
View details for Web of Science ID 000887092100001
View details for PubMedID 36428999
View details for PubMedCentralID PMC9688439
Protease- and cell type-specific activation of protease-activated receptor 2 in cutaneous inflammation
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Protease-activated receptor 2 (PAR2) signaling controls skin barrier function and inflammation, but the roles of immune cells and PAR2-activating proteases in cutaneous diseases are poorly understood.To dissect PAR2 signaling contributions to skin inflammation with new genetic and pharmacological tools.We found markedly increased numbers of PAR2+ infiltrating myeloid cells in skin lesions of allergic contact dermatitis (ACD) patients and in the skin of contact hypersensitivity (CHS) in mice, a murine ACD model for T cell-mediated allergic skin inflammation. Cell type-specific deletion of PAR2 in myeloid immune cells as well as mutation-induced complete PAR2 cleavage insensitivity significantly reduced skin inflammation and hapten-specific Tc1/Th1 cell response. Pharmacological approaches identified individual proteases involved in PAR2 cleavage and demonstrated a pivotal role of tissue factor (TF) and coagulation factor Xa (FXa) as upstream activators of PAR2 in both the induction and effector phase of CHS. PAR2 mutant mouse strains with differential cleavage sensitivity for FXa versus skin epithelial cell-expressed proteases furthermore uncovered a time-dependent regulation of CHS development with an important function of FXa-induced PAR2 activation during the late phase of skin inflammation.Myeloid cells and the TF-FXa-PAR2 axis are key mediators and potential therapeutic targets in inflammatory skin diseases.
View details for DOI 10.1111/jth.15894
View details for Web of Science ID 000866278800001
View details for PubMedID 36161697
Neutrophil-Specific Knockdown of beta 2 Integrins Impairs Antifungal Effector Functions and Aggravates the Course of Invasive Pulmonal Aspergillosis
FRONTIERS IN IMMUNOLOGY
2022; 13: 823121
β2-integrins are heterodimeric surface receptors that are expressed specifically by leukocytes and consist of a variable α (CD11a-d) and a common β-subunit (CD18). Functional impairment of CD18, which causes leukocyte adhesion deficiency type-1 results in an immunocompromised state characterized by severe infections, such as invasive pulmonary aspergillosis (IPA). The underlying immune defects have largely been attributed to an impaired migratory and phagocytic activity of polymorphonuclear granulocytes (PMN). However, the exact contribution of β2-integrins for PMN functions in-vivo has not been elucidated yet, since the mouse models available so far display a constitutive CD18 knockout (CD18-/- or CD18hypo). To determine the PMN-specific role of β2-integrins for innate effector functions and pathogen control, we generated a mouse line with a Ly6G-specific knockdown of the common β-subunit (CD18Ly6G cKO). We characterized CD18Ly6G cKO mice in-vitro to confirm the PMN-specific knockdown of β2-integrins. Next, we investigated the clinical course of IPA in A. fumigatus infected CD18Ly6G cKO mice with regard to the fungal burden, pulmonary inflammation and PMN response towards A. fumigatus. Our results revealed that the β2-integrin knockdown was restricted to PMN and that CD18Ly6G cKO mice showed an aggravated course of IPA. In accordance, we observed a higher fungal burden and lower levels of proinflammatory innate cytokines, such as TNF-α, in lungs of IPA-infected CD18Ly6G cKO mice. Bronchoalveolar lavage revealed higher levels of CXCL1, a stronger PMN-infiltration, but concomitantly elevated apoptosis of PMN in lungs of CD18Ly6G cKO mice. Ex-vivo analysis further unveiled a strong impairment of PMN effector function, as reflected by an attenuated phagocytic activity, and a diminished generation of reactive oxygen species (ROS) and neutrophil-extracellular traps (NET) in CD18-deficient PMN. Overall, our study demonstrates that β2-integrins are required specifically for PMN effector functions and contribute to the clearance of A. fumigatus by infiltrating PMN, and the establishment of an inflammatory microenvironment in infected lungs.
View details for DOI 10.3389/fimmu.2022.823121
View details for Web of Science ID 000813318000001
View details for PubMedID 35734179
View details for PubMedCentralID PMC9207500