MONOCYTIC BUT NOT GRANULOCYTIC MDSCS INCREASE WITH IBRUTINIB BUT NOT ACALABRUTINIB TREATMENT IN EM-TCL1 MICE WITH CLL, SUGGESTING A ROLE FOR ITK INHIBITION IN MONOCYTIC MDSCS
Author(s): ,
Arantxa Romero-Toledo
Affiliations:
Centre for Heamato-Oncology,Barts Cancer Institute,London,United Kingdom
,
Mark Schwarzbich
Affiliations:
Centre for Heamato-Oncology,Barts Cancer Institute,London,United Kingdom
,
Robin Sanderson
Affiliations:
Centre for Heamato-Oncology,Barts Cancer Institute,London,United Kingdom
John Gribben
Affiliations:
Centre for Heamato-Oncology,Barts Cancer Institute,London,United Kingdom
EHA Library. Romero-Toledo A. Jun 15, 2019; 266752; PS1135
Arantxa Romero-Toledo
Arantxa Romero-Toledo
Contributions
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Abstract

Abstract: PS1135

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

Myeloid derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells with the ability to suppress T cell function and promote Treg expansion. In humans, CLL cells can induce the conversion of monocytes to MDSCs provoking their accumulation in peripheral blood (PB) 1. MDSCs include two major subsets granulocytic (Gr) and monocytic (M)-MDSC. In mice, Gr-MDSCs and M-MDSC are defined as CD11b+Ly6G+Ly6Clo and CD11b+Ly6G-Ly6Chi, respectively. Both murine and human MDSCs express BTK. It has been demonstrated that treatment with the BTK inhibitor (BTKi), Ibrutinib modulates MDSC function in a murine breast cancer model and its use has been suggested for enhancing immune-based therapies in solid tumors2.

Aims

We aimed to determine the role of MDSCs in CLL engraftment and the impact of iIbrutinib and acalibrutinib (second generation BTKi) in these cell populations in vivo. CLL is associated with a tumour supported microenvironment and T cells exhibit multiple functional defects and features of exhaustion. These T cell defects in CLL are closely recapitulated in Em-TCL1 (TCL1) mice, and are induced in healthy mice by adoptive transfer (AT) of murine CLL cells.

Methods

To address this question in vivo C57/Bl6 animals 2.5 months of age were AT with 40x106 purified pooled TCL1 CLL B cells. When PB CLL load reach >10% animals were randomized (mean day 14) to either vehicle treatment (2% HPBD) Ibrutinib (0.15 mg/l in 2% HPBC) or Acalabrutinib treatment (0.15 mg/l in 2% HPBC) for 21 days. 15 animals per group were analysed. MDSC sub-populations were monitored weekly and splenic cells were isolated and characterized by flow cytometry.

Results

During CLL progression, the overall ratio of CD11b+ over non-B cells significantly decreased in PB from 4 weeks post AT when compared to age-matched WT controls (p<0.0001). At the same time, the ratios of both Gr- and M-MDSCs over non-B cells were significantly decreased (p<0.001) as the population of malignant CD19+CD5+ cells expanded in PB. After treatment, the CD11b+CD19- cell population was not affected by either ibrutinib or acalibrutinib treatments (ns) in spleens. There was an increased presence of M-MDSCs after Ibrutinib treatment (p<0.01), but not acalibrutinib (ns); whilst the presence of Gr-MDSCs increased with both treatments (p<0.001 and p<0.05 respectively). Finally, the population of CD11b+F4/80+ macrophages had a higher increase with acalibrutinib (p<0.001) than ibrutinib (p<0.05) in spleens after treatment.

Conclusion

Although MDSCs increase with CLL development in this model, the population of MDSC in PB disappears with CLL disease progression, likely due to the accelerated increment of the CLL population overtaking the tumour microenvironment.  When TCL1 AT mice are treated with BTKis, the provoked clearance of CLL cells in secondary lymphoid organs allows the recovery of MDSCs at site. We speculate that the particular increase in M-MDSC subpopulation in spleens is ITK dependant, since we only observe this after ibrutinib and not acalibrutinib treatment. This provides the rationale for our ongoing preclinical studies of these populations in response to BTKis currently used for the treatment of CLL.

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research

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