Leukemia Associated Macrophages and Neutrophils Contribute to Immune Suppression through PD-L1 and Arginase in BCR-ABL1 Chronic Myeloid Leukemia

The BCR-ABL1 fusion gene is the molecular hallmark of chronic myeloid leukemia (CML). Despite the success of oral tyrosine kinase inhibitors (TKIs), challenges remain in management of CML patients. Emerging immunotherapy provides potential for further improvement of patient outcome. Our current investigation in a transgenic mouse model of BCR-ABL1 CML revealed continuous increases in CD11b+Ly6C^Int PMN-MDSC, CD11b+Ly6C^High M-MDSC and F4/80+ macrophages during CML progression. Concurrently, significant reductions occurred in the levels of immune effector T, B and NK cells. This immune suppression phenomenon was consistent in both primary leukemia induction and following leukemia cell transplantation. PD-L1 was exclusively upregulated in M-MDSCs/macrophages, accompanied by remarkable increases of PD1+ CD4 and CD8 T cells. When co-cultured with CD4+ T cells, PMN-MDSCs significantly inhibited their division. Mechanistically, there is a global activation of the immunosuppressive genes including Arg1, Entpd1 and S100a8/9 in PMN-MDSCs. Importantly, expression correlation assay and pharmacological inhibition indicate a direct regulation of those genes by BCR-ABL1. Furthermore, blocking BCR-ABL1 or arginases activities with inhibitors proved BCR-ABL1 directly regulated targets such as Arg1 in immune suppression. Taken together, our results indicate two different immune suppression mechanisms in a CML mouse model, through the immune suppressive PMN-MDSCs and PD-L1+ M-MDSCs/macrophages. Accordingly, combination treatment with ponatinib and anti-PD1 antibody not only provides rapid remission, but also better disease control after treatment discontinuation. This study, therefore, has revealed the detailed mechanisms underlying immune evasion of BCR-ABL1 CML cells, which justifies exploring combination treatment to improve the success rate of treatment free remission of CML.

No relevant conflicts of interest to declare.