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Plasma cells (PCs) in bone marrow (BM) play an important role in both protective and pathogenic humoral immune responses, e.g. in various malignant and non-malignant diseases such as multiple myeloma, primary and secondary immunodeficiencies and autoimmune diseases. Dedicated microenvironmental niches in the BM provide PCs with biomechanical and soluble factors that support their long-term survival. There is a high need for appropriate and robust model systems to better understand PCs biology, to develop new therapeutic strategies for PCs-related diseases and perform targeted preclinical studies with high predictive value. Most preclinical data have been derived from in vivo studies in mice, as in vitro studies of human PCs are limited due to restricted survival and functionality in conventional 2D cultures that do not reflect the unique niche architecture of the BM. We have developed a microphysiological, dynamic 3D BM culture system (BM-MPS) based on human primary tissue (femoral biopsies), mechanically supported by a hydrogel scaffold casing. While a bioinert agarose casing did not support PCs survival, a photo-crosslinked collagen-hyaluronic acid (Col-HA) hydrogel preserved the native BM niche architecture and allowed PCs survival in vitro for up to 2 weeks. Further, the Col-HA hydrogel was permissive to lymphocyte migration into the microphysiological system´s circulation. Long-term PCs survival was related to the stable presence in the culture of soluble factors, as APRIL, BAFF, and IL-6. Increasing immunoglobulins concentrations in the medium confirm their functionality over culture time. To the best of our knowledge, this study is the first report of successful long-term maintenance of primary-derived non-malignant PCs in vitro . Our innovative model system is suitable for in-depth in vitro studies of human PCs regulation and exploration of targeted therapeutic approaches such as CAR-T cell therapy or biologics., (Creative Commons Attribution license.)

Hodgkin-Reed-Sternberg cells (HRSCs) in classic Hodgkin Lymphoma (HL) frequently lack expression of human leukocyte antigen class I (HLA-I), considered to hamper activation of cytotoxic T cells in the tumor microenvironment (TME). Here, we demonstrate HLA-I expression on HRSCs to be a strong determinant of TME composition whereas expression of HLA-II was associated with only minor differential gene expression in the TME. In HLA-I-positive HL the HRSC content and expression of CCL17/TARC in HRSCs are low, independent of the presence of Epstein-Barr virus in HRSCs. Additionally, HLA-I-positive HL shows a high content of CD8+ cytotoxic T cells. However, an increased expression of the inhibitory immune checkpoint LAG3 on CD8+ T cells in close proximity to HRSCs is observed. Suggesting interference with cytotoxic activity, we observed an absence of clonally expanded T cells in the TME. While HLA-I-positive HL is not associated with an unfavorable clinical course in our cohorts, they share features with the recently described H2 subtype of HL. Given the major differences in TME composition, immune checkpoint inhibitors may differ in their mechanism of action in HLA-I-positive compared to HLA-I-negative HL., Competing Interests: Dr von Tresckow is an advisor or consultant for Allogene, BMS/Celgene, Cerus, Incyte, IQVIA, Gilead Kite, Lilly, Miltenyi, Novartis, Noscendo, Pentixapharm, Roche, Amgen, Pfizer, Takeda, Merck Sharp & Dohme, and Gilead Kite; has received honoraria from AstraZeneca, BMS, Incyte, Lilly, Novartis, Roche Pharma AG, Takeda, and Merck Sharp & Dohme; reports research funding from Novartis (Inst), Merck Sharp & Dohme (Inst), and Takeda (Inst); and reports travel support from AbbVie, AstraZeneca, Gilead Kite, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis all outside the submitted work. Dr P. Borchmann reports grants from BMS during the conduct of the study. Dr Engert reports grants and nonfinancial support from BMS during the conduct of the study, and personal fees from Takeda, BMS, and MSD outside the submitted work. Dr Bröckelmann is an advisor or consultant for BeiGene, BMS, MSD, Stemline, and Takeda, received honoraria from BeiGene, BMS, MSD, Stemline, and Takeda, received travel support from BeiGene, Celgene, and Takeda, and reports research funding from BeiGene (Inst), BMS (Inst), MSD (Inst) and Takeda (Inst). Dr Klapper reports grants from Roche, Amgen, Takeda, Incyte, and Regeneron paid to his institution outside the submitted work. The remaining authors declare no conflicts of interest., (© 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)