Hypermature but dysfunctional NK Cells is associated with Advanced Myelofibrosis — ASN Events
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  3. Hypermature but dysfunctional NK Cells is associated with Advanced Myelofibrosis

Hypermature but dysfunctional NK Cells is associated with Advanced Myelofibrosis (#197)

Mariana Medeiros 1 2 , Camila Araújo Bernardino Garcia 1 2 , Larissa Sarri Binelli 1 2 , Allana Guimarães de Carvalho 1 2 , Letícia Olops Marani 1 2 , Priscila Santos Scheucher 1 , Josiane Lílian dos Santos Schiavinato 1 , Leonardo Carvalho Palma 1 , Pedro Manoel Marques Garibaldi 1 , Lorena Lobo de Figueiredo-Pontes 1 2
  1. Hematology Division, Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirao Preto Medical School at University of Sao Paulo, Ribeirão Preto, Sao Paulo, Brasil
  2. Ribeirão Preto Blood Center Foundation, University of São Paulo, Ribeirão Preto, Sao Paulo, Brasil

Myelofibrosis (MF), driven by JAK/STAT signaling mutations in hematopoietic stem cells, has the worst survival rates among myeloproliferative neoplasms (MPNs), worsening from pre-fibrotic MF (PFMF) to overt MF (OMF) that often precedes acute myeloid leukemia. Natural Killer (NK) cells have phenotypical and functional alterations that predominate in MF when compared to other classical MPNs, suggesting that the immune content may contribute to disease burden. To characterize the NK cells of MF patients, PBMC from 9 PFMF and 9 OMF, and 9 healthy donors (controls: CT) were analyzed by flow cytometry to profile: NK cell frequency and subtypes (CD45hiCD3-CD19-CD56brightCD16-; CD45hiCD3-CD19-CD56dimCD16+; NK maturation [CD57+ hypermature; CD11b-CD27- tolerant (DN), CD27+CD11b- immature secretory (IS), CD27+CD11b+ mature secretory (MS), CD11b+CD27- cytotoxic]. NK cytotoxic capacity was measured by quantifying dead/K562 target cells after PBMC co-culture.Top of FormBottom of Form CD56bright NK cells were increased and CD56dim decreased in MF vs CT (CD56bright: CT 3.4±2.6%, MF 17.7±17.9%, p<0.001; CD56dim: CT 82.7±7.6%, MF 53.4±25%, p<0.001). NK maturation profiles in MF showed increased immature NK cells (DN: CT 4.5±3.5%, MF 13.9±8.7%, p=0.002; IS: CT 0.2±0.3%, MF 1.2±1.2%, p=0.03), and lower cytotoxic NK cells (CT 92.1±3.8%, MF 77.3±11.2%, p<0.001). Hypermature NK frequency was higher in OMF compared to PFMF (PFMF 45.5±25.7%, OMF 61.5±25.9%, p=0.04). In agreement, reduced NK cytotoxic capacity was observed in MF (CT 81.8±4.2%, MF 30.1±7.76%, p=0.02) and slightly increased cytotoxicity accompanied fibrosis (p=0.7). More advanced MF has a higher degree of fibrosis, which leads to an inflammatory profile in the disease, activating NK cells and result in a more mature but cytotoxic-deficient profile due to exhaustion. The results shed light on the mechanisms involved in MF progression, suggesting that changes in the maturation profile of cytotoxic cells is associated with disease progression, thus inspiring new therapies that target antitumoral cells from the leukemic environment.