Immunosuppression and Outcomes in Acute Myeloid Leukemia

Ferraro, F.; Miller, C.; Christensen, K.; Helton, N. M.; O'Laughlin, M.; Fronick, C. C.; Fulton, R. S.; Kohlschmidt, J.; Eisfeld, A.-K.; Bloomfield, C. D.; Ramakrishnan, S. M.; Day, R. B.; Wartman, L. D.; Uy, G. L.; Welch, J. S.; Christopher, M. J.; Heath, S. E.; Baty, J. D.; Schuelke, M. J.; Payton, J. E.; Spencer, D. H.; Rettig, M. P.; Link, D. C.; Walter, M. J.; Peter, W.; DiPersio, J. F.; Ley, T. J.

doi:10.1101/2021.09.03.458879

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bioRxiv · 10.1101/2021.09.03.458879

Immunosuppression and Outcomes in Acute Myeloid Leukemia

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Abstract

Acute myeloid leukemia (AML) patients rarely have long first remissions (> 5 years) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, short remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing and functional immunologic studies, we characterized 28 Normal Karyotype (NK)-AML patients with >5 year first remissions after chemotherapy (Long First Remissions, LFR) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 years (Standard First Remissions, SFR). Our combined analyses indicated that genetic risk profiling at presentation (as defined by ELN 2017 Criteria) was not sufficient to explain the outcomes of many SFR cases. Single cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T-cells expressed an exhaustion signature and were resistant to activation by T-cell receptor stimulation in the presence of autologous AML cells. T-cell activation could be restored by removing the AML cells, or blocking the inhibitory MHC Class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T-cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.

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Ferraro, F., Miller, C., Christensen, K., Helton, N. M., O'Laughlin, M., Fronick, C. C., Fulton, R. S., Kohlschmidt, J., Eisfeld, A.-K., Bloomfield, C. D., Ramakrishnan, S. M., Day, R. B., Wartman, L. D., Uy, G. L., Welch, J. S., Christopher, M. J., Heath, S. E., Baty, J. D., Schuelke, M. J., Payton, J. E., Spencer, D. H., Rettig, M. P., Link, D. C., Walter, M. J., Peter, W., DiPersio, J. F., Ley, T. J.. 2021-09-06. Immunosuppression and Outcomes in Acute Myeloid Leukemia. https://doi.org/10.1101/2021.09.03.458879

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