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Wilcoxon 695 matched pairs sign rank test. *** p < .001. Red lines represent medians. (B) Cell cycle 696 analysis (BrdU/PI) of PB MCL cells (n = 16) after 7 days of co-cultures with monocytes 697 according to their molecular subtypes ,
, C) Percentage 699 of live cells (AnnexinV staining, n = 4, left panel) and cell cycle analysis (BrdU/PI, n = 5, right 700 panel) of PB MCL cells cultured alone or in contact with autologous or allogeneic monocytes 701 for 7 days
, Figure 2. MCL cells polarize monocytes into specific M?MCL with M2-like features, p.704
, An ascendant hierarchical clustering was constructed with ward.D2 method of Euclidian 705 distance. M2 were generated from human monocytes cultured with CSF1/IL-10 (see 706 methods, M2' with CSF1 alone (GSE20484) and M1 with LPS/IFNg (GSE95405) (B), p.707
, Radarchart representation of the cibersort signature for M?MCL and MCL-infiltrated 708
, macrophages in lymph nodes. (C, left panel) CD163 Mean Fluorescence Intensity ratio 709 assessed by flow cytometry for M1 (n = 6), M2 (n = 6) and M?MCL (n = 9
, right panel) IGF1, IL10 and IL6 induction 711 measured by qRT-PCR (relative to undifferentiated human monocytes) for M1 (n = 3), M2 (n 712 = 3) and M?MCL (n = 5) macrophages. t-test
, Figure 3. MCL cells express the M2-polarising factors CSF1 and IL-10. (A) Expression of 715 CSF1 and IL10 in MCL cells
, GEP public databases (see Methods). Mann-Whitney test. n.s, not significant, p.717
, B) qRT-PCR analysis of CSF1 and IL10 gene expression in 9 MCL cell 718 lines (realized in triplicate) and (C) twenty CD19 + MCL samples purified from PB. Expression 719 was normalized to Granta cell line. (D) Concentration of CSF1 and IL-10 proteins evaluated 720 by ELISA in the supernatant of M?MCL/MCL co-culture (7 days, n = 10). (E) Percentage of 721 lived CD14 cells, p.722
, 001 (F) Percentage 725 of primary MCL live cells in coculture with monocytes with or without GW2580 treatment 726 (1µM) (n = 8). Cell death was assessed by Annexin-V staining. Wilcoxon matched pairs sign 727 rank test, anti-IL-10R antibodies (5µg/mL). Paired t-test *p < .05 **p < .01 ***p <
, Ibrutinib counteracts MCL/M?MCL dialogue through inhibition of CSF1, p.730
, Gene 732 expression has been normalized to the non-treated control condition of each cell line 733 (realized in triplicate) (B) Concentration of CSF1 and IL-10 proteins evaluated by ELISA in 734 the supernatant of Mino and Granta cells with or without ibrutinib treatment
, Gating strategy to evaluate the CD163 expression on CD14 + 736 after 3 days of co-culture between monocytes and Mino or Granta cells with or without 737 ibrutinib treatment (72h; 0.5µM) (lower panel) CD163 MFI modulation on CD14+ cells 738 representing 3 independent experiments. (D) Percentage of primary MCL live cells in 739 coculture with monocytes (Annexin-V staining) with or without ibrutinib treatment
, Wilcoxon matched pairs sign rank test. *** p < .01. (E) Cell cycle analysis 741 (BrdU/PI) of primary MCL cells after 5 days of co-cultures with monocytes with or without 742 ibrutinib treatment
, A) Plasma concentration of CSF1 and IL-10 proteins in MCL 746 patients (n = 28) and age-matched healthy donors, Figure 5. CD163 modulation on circulating monocytes in vivo might be an early marker 745 of ibrutinib response, p.747
, Mean fluorescence intensity ratio (MFIr) of CD163 on circulating monocytes (CD14 + cells
, MCL patients (n = 32) compare to age-matched HD (n = 8). Mann-Whitney test, p.749
, B) Plasma concentration of CSF1 and IL-10 and CD163 MFIr modulation 750 on monocytes (CD14 + ) of patient treated with anti-CD20 and ibrutinib (Clinical trial: 751 NTC02558816)
, Figure 6. CSF1R as a potential therapeutic target for ibrutinib resistant patients, p.756
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, MCL cells were cocultured with monocytes and treated with low doses of ibrutinib (125 nM) 760 or GW2580 (125 nM) or both for 72h. Cell death was assessed by assessed by Annexin-V 761 staining