Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy

Katie Maurer; Cameron Y. Park; Shouvik Mani; Mehdi Borji; Florian Raths; Kenneth H. Gouin; Livius Penter; Yinuo Jin; Jia Yi Zhang; Crystal S. Shin; James R. Brenner; Jackson Southard; Sachi Krishna; Wesley S. Lu; Haoxiang Lyu; Domenic Abbondanza; Chanell Mangum; Lars Rønn Olsen; Michael J. Lawson; Martin M. Fabani; Donna S Neuberg; Pavan Bachireddy; Eli N. Glezer; Samouil L. Farhi; Shuqiang Li; Kenneth J. Livak; Jerome Ritz; Robert J. Soiffer; Catherine J. Wu; Elham Azizi

doi:10.1126/sciimmunol.adr0782

Cancer BiologyScience ImmunologyJan 24, 2025

Peer-reviewed journal article

Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy

Katie Maurer iD, Cameron Y. Park iD, Shouvik Mani iD, Mehdi Borji iD, Florian Raths, Kenneth H. Gouin iD, Livius Penter iD, Yinuo Jin iD, Jia Yi Zhang, Crystal S. Shin iD, James R. Brenner iD, Jackson Southard iD, Sachi Krishna iD, Wesley S. Lu iD, Haoxiang Lyu iD, Domenic Abbondanza iD, Chanell Mangum iD, Lars Rønn Olsen iD, Michael J. Lawson iD, Martin M. Fabani iD, Donna S Neuberg iD, Pavan Bachireddy iD, Eli N. Glezer, Samouil L. Farhi iD, Shuqiang Li iD, , Elham Azizi iD

Abstract

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.

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