Maximilian Haist

All Publications

• T cell-mediated curation and restructuring of tumor tissue coordinates an effective immune response. Cell reports Hickey, J. W., Haist, M., Horowitz, N., Caraccio, C., Tan, Y., Rech, A. J., Baertsch, M. A., Rovira-Clavé, X., Zhu, B., Vazquez, G., Barlow, G., Agmon, E., Goltsev, Y., Sunwoo, J. B., Covert, M., Nolan, G. P. 2023; 42 (12): 113494

  Abstract

  Antigen-specific T cells traffic to, are influenced by, and create unique cellular microenvironments. Here we characterize these microenvironments over time with multiplexed imaging in a melanoma model of adoptive T cell therapy and human patients with melanoma treated with checkpoint inhibitor therapy. Multicellular neighborhood analysis reveals dynamic immune cell infiltration and inflamed tumor cell neighborhoods associated with CD8+ T cells. T cell-focused analysis indicates T cells are found along a continuum of neighborhoods that reflect the progressive steps coordinating the anti-tumor immune response. More effective anti-tumor immune responses are characterized by inflamed tumor-T cell neighborhoods, flanked by dense immune infiltration neighborhoods. Conversely, ineffective T cell therapies express anti-inflammatory cytokines, resulting in regulatory neighborhoods, spatially disrupting productive T cell-immune and -tumor interactions. Our study provides in situ mechanistic insights into temporal tumor microenvironment changes, cell interactions critical for response, and spatial correlates of immunotherapy outcomes, informing cellular therapy evaluation and engineering.

  View details for DOI 10.1016/j.celrep.2023.113494

  View details for PubMedID 38085642

• Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG. Journal for immunotherapy of cancer Haist, M., Stege, H., Rogall, F., Tan, Y., von Wasielewski, I., Klespe, K. C., Meier, F., Mohr, P., Kähler, K. C., Weichenthal, M., Hauschild, A., Schadendorf, D., Ugurel, S., Lodde, G., Zimmer, L., Gutzmer, R., Debus, D., Schilling, B., Kreuter, A., Ulrich, J., Meiss, F., Herbst, R., Forschner, A., Leiter, U., Pfoehler, C., Kaatz, M., Ziller, F., Hassel, J. C., Tronnier, M., Sachse, M., Dippel, E., Terheyden, P., Berking, C., Heppt, M. V., Kiecker, F., Haferkamp, S., Gebhardt, C., Simon, J. C., Grabbe, S., Loquai, C. 2023; 11 (9)

  Abstract

  Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy.For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments.Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004).BRAFmut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.

  View details for DOI 10.1136/jitc-2023-007630

  View details for PubMedID 37730278

  View details for PubMedCentralID PMC10510881

• Response to primary chemoradiotherapy of locally advanced oropharyngeal carcinoma is determined by the degree of cytotoxic T cell infiltration within tumor cell aggregates. Frontiers in immunology Haist, M., Kaufmann, J., Kur, I. M., Zimmer, S., Grabbe, S., Schmidberger, H., Weigert, A., Mayer, A. 2023; 14: 1070203

  Abstract

  Effective anti-tumor immune responses are mediated by T cells and require organized, spatially coordinated interactions within the tumor microenvironment (TME). Understanding coordinated T-cell-behavior and deciphering mechanisms of radiotherapy resistance mediated by tumor stem cells will advance risk stratification of oropharyngeal cancer (OPSCC) patients treated with primary chemoradiotherapy (RCTx).To determine the role of CD8 T cells (CTL) and tumor stem cells for response to RCTx, we employed multiplex immunofluorescence stains on pre-treatment biopsy specimens from 86 advanced OPSCC patients and correlated these quantitative data with clinical parameters. Multiplex stains were analyzed at the single-cell level using QuPath and spatial coordination of immune cells within the TME was explored using the R-package Spatstat.Our observations demonstrate that a strong CTL-infiltration into the epithelial tumor compartment (HR for overall survival, OS: 0.35; p<0.001) and the expression of PD-L1 on CTL (HR: 0.36; p<0.001) were both associated with a significantly better response and survival upon RCTx. As expected, p16 expression was a strong predictor of improved OS (HR: 0.38; p=0.002) and correlated with overall CTL infiltration (r: 0.358, p<0.001). By contrast, tumor cell proliferative activity, expression of the tumor stem cell marker CD271 and overall CTL infiltration, regardless of the affected compartment, were not associated with response or survival.In this study, we could demonstrate the clinical relevance of the spatial organization and the phenotype of CD8 T cells within the TME. In particular, we found that the infiltration of CD8 T cells specifically into the tumor cell compartment was an independent predictive marker for response to chemoradiotherapy, which was strongly associated with p16 expression. Meanwhile, tumor cell proliferation and the expression of stem cell markers showed no independent prognostic effect for patients with primary RCTx and thus requires further study.

  View details for DOI 10.3389/fimmu.2023.1070203

  View details for PubMedID 37187729

  View details for PubMedCentralID PMC10175951

• Neutrophil-Specific Knockdown of beta 2 Integrins Impairs Antifungal Effector Functions and Aggravates the Course of Invasive Pulmonal Aspergillosis FRONTIERS IN IMMUNOLOGY Haist, M., Ries, F., Gunzer, M., Bednarczyk, M., Siegel, E., Kuske, M., Grabbe, S., Radsak, M., Bros, M., Teschner, D. 2022; 13: 823121

  Abstract

  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

• Novel methods of multiparametric tissue diagnostics ONKOLOGIE Mayer, A., Haist, M. 2023; 29 (12): 1069-1077

  View details for DOI 10.1007/s00761-023-01425-7

  View details for Web of Science ID 001187929000001

• Spatial Dissection of the Bone Marrow Microenvironment in Multiple Myeloma By High Dimensional Multiplex Tissue Imaging Baertsch, M., Brobeil, A., Hickey, J., Haist, M., Poos, A., Lu, G., Kuswanto, W., Schuerch, C., Voehringer, H., Huber, W., Mechtersheimer, G., Mueller-Tidow, C., Schirmacher, P., Weisel, K., Fenk, R., Goldschmidt, H., Goltsev, Y., Raab, M. S., Weinhold, N., Nolan, G. P. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-189255

  View details for Web of Science ID 001159306700086

• Quantification of invasion patterns as a predictive factor for the therapeutic response of oropharyngeal squamous cell carcinoma to radiochemotherapy Kaufmann, J., Haist, M., Kur, I., Zimmer, S., Hagemann, J., Matthias, C., Grabbe, S., Schmidberger, H., Weigert, A., Mayer, A. SPRINGER HEIDELBERG. 2023: S35-S36

  View details for Web of Science ID 001045118200063

• Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better? Cancer metastasis reviews Haist, M., Stege, H., Kuske, M., Bauer, J., Klumpp, A., Grabbe, S., Bros, M. 2023

  Abstract

  The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens.

  View details for DOI 10.1007/s10555-023-10097-z

  View details for PubMedID 37022618

• 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. Cancers Haist, M., Stege, H., Lang, B. M., Tsochataridou, A., Salzmann, M., Mohr, P., Schadendorf, D., Ugurel, S., Placke, J., Weichenthal, M., Gutzmer, R., Leiter, U., Kaatz, M., Haferkamp, S., Berking, C., Heppt, M., Tschechne, B., Schummer, P., Gebhardt, C., Grabbe, S., Loquai, C. 2022; 14 (22)

  Abstract

  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. JCI insight Klaus, T., Wilson, A. S., Vicari, E., Hadaschik, E., Klein, M., Helbich, S. S., Kamenjarin, N., Hodapp, K., Schunke, J., Haist, M., Butsch, F., Probst, H. C., Enk, A. H., Mahnke, K., Waisman, A., Bednarczyk, M., Bros, M., Bopp, T., Grabbe, S. 2022

  Abstract

  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 CELLS Aulasevich, N., Haist, M., Foersch, S., Weidenthaler-Barth, B., Mailaender, V. 2022; 11 (22)

  Abstract

  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 Fleischer, M., Roehrig, N., Raker, V. K., Springer, J., Becker, D., Ritz, S., Bros, M., Stege, H., Haist, M., Grabbe, S., Haub, J., Becker, C., Reyda, S., Disse, J., Schmidt, T., Mahnke, K., Weiler, H., Ruf, W., Steinbrink, K. 2022

  Abstract

  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