Cytokines, Chemokines and Soluble Immune Checkpoint Inhibitors Profile in Chronic-CML Patients: Mechanisms Associated with Response to Treatment in the Era of TKI

Chronic Myeloid Leukemia (CML) is a hematological malignancy caused by translocation between chromosome 9 and 22 t(9;22) named as Philadelphia (Ph) chromosome through BCR-ABL1oncoprotein. CML exhibit high sensitivity toward targeted therapy, genomic abnormalities and immune editing. The gold standard treatment for CML is Tyrosine Kinase inhibitor (TKI) targeting BCR-ABL1. TKI is a life-long treatment that required routine monitoring protocol. CML patients’ response is monitored by molecular quantification of BCR-ABL1 mRNA using RT-qPCR techniques, reported in the International Scale (IS) reporting system, and classified into: optimal, warning, and failure. In this thesis, we report on karyotyping of CML patients at diagnosis and present data on quantification of cytokines, chemokines, and soluble immune checkpoint inhibitors in 5 optimal and 6 warning CML patients after at least 6 months of TKI administration. We further investigated the long-term inhibitory effect of Additional Chromosome Abnormalities (ACA) on the immune system in shaping the patients’ response to TKI. Our results showed a deferential immune profile in the warning group indicated by 1) downregulation in cytokines and chemokines required for activation, differentiation, recruitment, maturation of immune effector cells, such as TNF-α, MIP-1α, MIP-1 β, IL-7, IL-1β, IL-4, IL-5, IL-13, IL-17A which may indicate an immune escape mechanism from TKI in this group; 2) upregulation of I-TAC a marker associated with tumor growth. Interestingly, one patient from the warning group (G1-P12) who carries additional chromosomal abnormality associated with poor prognosis, exhibited also upregulation of soluble immune checkpoint inhibitors (MICA/B, CD73, CD96, LAG3, PD-L2, BTLA, CD80) known to be associated with bad prognosis. In conclusion, we have identified a common deferential cytokine/chemokine profile in the warning group that may predict the response of CML patients to TKI treatment.