Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy.
Katie MaurerCameron Y ParkShouvik ManiMehdi BorjiLivius PenterYinuo JinJia Yi ZhangCrystal ShinJames R BrennerJackson SouthardSachi KrishnaWesley LuHaoxiang LyuDomenic AbbondanzaChanell MangumLars Rønn OlsenDonna S NeubergPavan BachireddySamouil L FarhiShuqiang LiKenneth J LivakJerome RitzRobert J SoifferCatherine J WuElham AziziPublished in: bioRxiv : the preprint server for biology (2024)
Understanding how intra-tumoral immune populations coordinate to generate anti-tumor responses following therapy can guide precise treatment prioritization. We performed systematic dissection of an established adoptive cellular therapy, donor lymphocyte infusion (DLI), by analyzing 348,905 single-cell transcriptomes from 74 longitudinal bone-marrow samples of 25 patients with relapsed myeloid leukemia; a subset was evaluated by protein-based spatial analysis. In acute myelogenous leukemia (AML) responders, diverse immune cell types within the bone-marrow microenvironment (BME) were predicted to interact with a clonally expanded population of ZNF683 + GZMB + CD8+ cytotoxic T lymphocytes (CTLs) which demonstrated in vitro specificity for autologous leukemia. This population, originating predominantly from the DLI product, expanded concurrently with NK and B cells. AML nonresponder BME revealed a paucity of crosstalk and elevated TIGIT expression in CD8+ CTLs. Our study highlights recipient BME differences as a key determinant of effective anti-leukemia response and opens new opportunities to modulate cell-based leukemia-directed therapy.
Keyphrases
- bone marrow
- acute myeloid leukemia
- single cell
- mesenchymal stem cells
- cell therapy
- stem cells
- allogeneic hematopoietic stem cell transplantation
- acute lymphoblastic leukemia
- low dose
- high throughput
- poor prognosis
- dendritic cells
- intensive care unit
- liver failure
- small molecule
- multiple myeloma
- immune response
- hepatitis b virus
- african american
- platelet rich plasma
- replacement therapy
- anti inflammatory