Myeloid-Derived Suppressive Cells Belonging to the Leukemic Clone Account for Immunosuppression In CMML

Abstract 3997

We have shown previously that cells identified as monocytes in the peripheral blood of patients with chronic myelomonocytic leukemia (CMLL) included a variable proportion of CD14-negative, CD24-positive immature granulocytes. These cells synthesize and secrete alpha-defensin 1–3 that inhibit M-CSF-driven monocyte differentiation into macrophages through interaction with the P2Y6 purinergic receptor (Droin N et al, Blood 2010).

In the present study, we show that these CD14-,CD24+ immature granulocytes also inhibit the proliferation of autologous lymphocytes activated with anti-CD3 and anti-CD28 antibodies through cell-cell contact. This functional property suggested that these cells could be “myeloid-derived suppressive cells” (MDSC), which was supported by their phenotype that included expression of CD15 marker at their surface and survivin, S100A8 and S100A9, Cyclin D2 and Cyclin D3 at the mRNA level. STAT3 and STAT6 were found constitutively phosphorylated in these immature granulocytes that responded to Toll-like receptor agonists such as LPS or Pam-6. CD14-positive monocytes of the leukemic clone activated these MDSC through production of IL-13 and induction of arginase 1 mRNA, which could be reproduced by recombinant IL-13. On the other hand, activation of these MDSC did not require induction of the nitric oxide synthase mRNA, in agreement with their granulocytic origin.

We were able to generate immature myeloid cells expressing CD24 with morphology similar to that of peripheral blood MDSC by in vitro culture of various subpopulations of bone marrow CD34-positive cells obtained from CMML patients, including the most immature CD34+/CD38-/CD90+ cells. Furthermore, generation of these cells could be recapitulated in vivo by xenotransplantation of CMML CD34+ cells in NOG mice, albeit with lower efficacy than CD14+ cells. In patients with high grade CMML included in a phase II clinical trial, decitabine was observed to decrease both CD14+,CD24- monocytes and CD14-,CD24+ immature granulocytes.

Altogether, these data suggest that CMML initiating cells generate CD14-positive monocytes and, in most patients, an additional population of CD14-negative immature granulocytes with suppressive properties towards innate and acquired immune response. Generation of these cells may account for the high sensitivity of CMML patients to autoimmune and infectious diseases.