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

Maurer, K.; Park, C.; Mani, S.; Borji, M.; Penter, L.; Jin, Y.; Zhang, J. Y.; Shin, C.; Brenner, J. R.; Southard, J.; Krishna, S.; Lu, W.; Lyu, H.; Abbondanza, D.; Mangum, C.; Olsen, L. R.; Neuberg, D. S.; Bachireddy, P.; Farhi, S. L.; Li, S.; Livak, K. J.; Ritz, J.; Soiffer, R. J.; Wu, C. J.; Azizi, E.

doi:10.1101/2024.02.09.579677

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bioRxiv · 10.1101/2024.02.09.579677

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

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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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Maurer, K., Park, C., Mani, S., Borji, M., Penter, L., Jin, Y., Zhang, J. Y., Shin, C., Brenner, J. R., Southard, J., Krishna, S., Lu, W., Lyu, H., Abbondanza, D., Mangum, C., Olsen, L. R., Neuberg, D. S., Bachireddy, P., Farhi, S. L., Li, S., Livak, K. J., Ritz, J., Soiffer, R. J., Wu, C. J., Azizi, E.. 2024-02-12. Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy. https://doi.org/10.1101/2024.02.09.579677

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