PS1169 CYTOKINE AND ARGINASE‐1 EXPRESSION DYNAMICS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA REVEALS EARLY MOLECULAR RESPONSE TO IMATINIB
Authors: Bestach Y. , Toloza M.J. , Mattos A. Enrico , Larripa I. , Belli C. 
Published: June 2019

Background:Imatinib remains as the preferred tyrosine kinase inhibitor (TKI) to treat chronic myeloid leukaemia (CML) patients. Besides its direct action targeting BCR‐ABL1, TKI therapy may also influence the anti‐tumour response. A broadly compromised immune system has been described at time of diagnosis supporting for a suppression of anti‐CML immune responses. These abnormalities include an expansion of the suppressive immune cell populations, myeloid derived suppressor cells (MDSCs) and regulatory T cells (Treg), and dysfunctional effector NK‐ and T‐immune responses. On TKI treatments, CML patients seem to re‐activate their immune system restoring the effector‐mediated immune surveillance.Aims:To describe TNF, IFNG, IL6, IL10, TGBF1, and ARG1 gene expression dynamic regarding molecular response to imatinib, since previous studies were designed by different approaches, criteria for timing and longitudinally studies are scare or missing.Methods:We analysed 106 peripheral blood samples of 64 CML patients, with multiple samples of 34 serially followed, and 26 of healthy donors. Were included patients at diagnosis (n = 23) and on imatinib 400 mg at 3 months (n = 41), 6 months (n = 42) classified according to the molecular response. An aliquot of the stored sample used to monitor BCR‐ABL1 level was retro‐transcribed to cDNA and TNF, IFNG, IL6, IL10, TGFB1 and ARG1 gene expression was quantified by PCR real time.Results:For patients at diagnosis, the expression of TNF, IFNG, IL6, IL10 and TGFB1 was significantly decreased when compared with healthy controls (Mann‐Whitney test p = 0.0336, p < 0.0001, p = 0.0007, p < 0.0001 and p = 0.0001, respectively); while ARG1 was significantly increased (Mann‐Whitney test p < 0.0001). The level of ARG1 expression correlated with the level of IL10 and TGFB1 expressions (Spearman r = 0.54, p = 0.0368 and r = 0.74, p = 0.0057, respectively), and IL10 with TGFB1 expression (Spearman: r = 0.65, p = 0.0087). Once imatinib therapy was initiated, those patients who achieved an early molecular response (EMR, BCR‐ABL1 ≤10% at 3 months) significantly increased the expression of the pro‐inflammatory cytokines TNF and IL6 when compared with healthy controls, and the ARG1 expression decreased to control levels. At 6 months, the enhancement of TNF and IL6 was observed in either responders (BCR‐ABL1 <1%) or non‐responders (≥1%), whereas the decrease of ARG1 expression was similar to control levels just in responders. At both 3 and 6 months of treatment, TNF correlated with IL6 expression only in responders (Spearman: r = 0.48, p = 0.0222; and r = 0.57, p = 0.0168, respectively). Furthermore, the longitudinal analysis between diagnosis and 3 months on therapy, those patients who achieve an EMR showed a statistically significant increase of 3 and 13 folds of TNF and IL6, respectively, and a significant 22‐fold decrease of ARG1 (Wilcoxon test: p = 0.0444, p = 0.0038 and p = 0.0094, respectively).Summary/Conclusion:Our results are in agreement with a significant immune suppression in CML patients at diagnosis, mediated by MDSCs and their influence on Tregs; also with a stimulatory effect on the immune system after imatinib initiation, especially in those who responded at 3 months. The dynamic of cytokines and, principally, ARG1 may play a role as an immune biomarker to monitor the response to TKI allowing the differentiation of optimal responders.