Immunomodulatory Effects of Tyrosine Kinase Inhibitor In Vitro and In Vivo Study Elena Marinelli Busilacchi, Andrea Costantini, Nadia Viola, Benedetta.

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Immunomodulatory Effects of Tyrosine Kinase Inhibitor In Vitro and In Vivo Study Elena Marinelli Busilacchi, Andrea Costantini, Nadia Viola, Benedetta Costantini, Jacopo Olivieri, Luca Butini, Giorgia Mancini, Ilaria Scortechini, Martina Chiarucci, Monica Poiani, Antonella Poloni, Pietro Leoni, Attilio Olivieri Biology of Blood and Marrow Transplantation Volume 24, Issue 2, Pages 267-275 (February 2018) DOI: 10.1016/j.bbmt.2017.10.039 Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Changes in Treg frequencies and death rate proportions after exposure to TKIs in vitro. Lymphocytes were gated by forward scatter and side scatter profiles. Tregs were identified by the co-expression of CD3, CD4, and CD25 surface markers and FoxP3 intracellular marker (line plots, A-D). Dying cells were identified by the expression of the marker 7-amino actinomycin D (7ADD) on the surface of CD3, CD4, and CD25-positive cells (bar plots, E-H). Results are expressed as percentages on total CD25-positive cells. Means and standard deviations are reported. *P < .05; **P < .02. Biology of Blood and Marrow Transplantation 2018 24, 267-275DOI: (10.1016/j.bbmt.2017.10.039) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Naive Treg frequencies after exposure to TKIs in vitro. Lymphocytes were gated by forward scatter and side scatter profiles. Naive Tregs were identified by the expression of the marker CD45RA on the surface of CD3, CD4, CD25, and FoxP3-positive cells (line plots, A-D). Results are expressed as percentages on total Tregs. Means and standard deviations are reported. *P < .05; **P < .02. Biology of Blood and Marrow Transplantation 2018 24, 267-275DOI: (10.1016/j.bbmt.2017.10.039) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 T cell production of proinflammatory and immunomodulatory cytokines after exposure to TKIs in vitro. T cells were purified from PBMCs through positive selection by magnetic cell separation CD3 microbeads and cultured. Cytokine production was measured on cell culture supernatants; baseline values (pg/mL) are compared with results obtained after exposure of cells to increasing concentrations of each TKI. Means and standard deviations are reported. *P < .05; **P < .02. Biology of Blood and Marrow Transplantation 2018 24, 267-275DOI: (10.1016/j.bbmt.2017.10.039) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Lymphocyte subpopulations changes after exposure to nilotinib in vivo. PBMCs obtained from sr-cGVHD affected patients treated with nilotinib at different dose schedule were thawed, labeled with monoclonal antibodies, and examined by flow cytometry. Frequencies of T, B, and NK cell subset are shown. Average values and standard deviation at baseline (white bars) and after 90 days (light gray bars) and 180 days (dark gray bars) of therapy are reported. Values are expressed as percentage of total lymphocytes; changes induced by different nilotinib dose schedules are represented together. Biology of Blood and Marrow Transplantation 2018 24, 267-275DOI: (10.1016/j.bbmt.2017.10.039) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Modification of cytokine production after exposure to nilotinib in vivo. Cytokine concentrations were determined on plasma samples from nilotinib-treated patients after thawing. Average values and standard deviation at baseline (white bars) and after 90 days (light gray bars) and 180 days (dark gray bars) of therapy are reported. Changes induced by different nilotinib dose schedules are represented together. *P < .05; **P < .02. Biology of Blood and Marrow Transplantation 2018 24, 267-275DOI: (10.1016/j.bbmt.2017.10.039) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions