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Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2384-2396
Altered T-cell subset repertoire affects treatment outcome of patients with myelofibrosis
Ivo Veletic,1,* Sanja Prijic,1,2,* Taghi Manshouri,1 Graciela M. Nogueras-Gonzalez,3 Srdan Verstovsek,1 and Zeev Estrov1
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Clinical Department of Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb, Croatia and 3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
*IV and SP contributed equally to the study as co-first authors.
ABSTRACT
Phenotypic characterization of T cells in myelofibrosis is intriguing because of increased inflammation, markedly elevated pro-inflam- matory cytokines, and altered distribution of T-cell subsets. Constitutive activation of Janus kinase-2 (JAK2) in the majority of patients with myelofibrosis contributes to the expression of the pro- grammed cell death protein-1 (PD1) and T-cell exhaustion. We wondered whether T-cell activation affects treatment outcome of patients with myelofibrosis and sought to determine whether the JAK1/2 inhibitor rux- olitinib affects the activation of T-cell subsets. T cells from 47 myelofibro- sis patients were analyzed and the percentages of either helper (CD4+) or cytotoxic (CD8+) naïve, central memory, effector memory, or effector T cells; and fractions of PD1-expressing cells in each subset were assessed. Higher numbers of T cells co-expressing CD4/PD1 and CD8/PD1 were found in myelofibrosis patients than in healthy controls (n=28), and the T cells were significantly skewed toward an effector phenotype in both CD4+ and CD8+ subsets, consistent with a shift from a quiescent to an activated state. Over the course of ruxolitinib treatment, the distribution of aberrant T-cell subsets significantly reversed towards resting cell phe- notypes. CD4+ and CD8+ subsets at baseline correlated with monocyte and platelet counts, and their PD1+ fractions correlated with leukocyte counts and spleen size. Low numbers of PD1+/CD4+ and PD1+/CD8+ cells were associated with complete resolution of palpable splenomegaly and improved survival rate, suggesting that low levels of exhausted T cells confer a favorable response to ruxolitinib treatment.
Introduction
Primary or secondary myelofibrosis (MF) is characterized by a significant immune deregulation.1,2 In the vast majority of patients with MF, Janus kinase (JAK)-2 is constitutively activated.3 As a result, MF neoplastic cells produce high levels of inflammatory cytokines and pentraxins that contribute to the induction of pro- gressive bone marrow (BM) fibrosis, debilitating constitutional symptoms, and poor prognosis in MF patients.4,5 Cytokines, such as interleukin (IL)-1, IL-6 and IL- 8, modulate T-cell activation and immune function through the activation of JAK2 and its downstream signal transducer and activator of transcription (STAT) path- ways.6,7 The JAK1/2 inhibitor ruxolitinib alleviates constitutional symptoms in MF patients, primarily by profound suppression of inflammation.8 Although it is known that JAK-STAT signaling modifies T-helper cell activity and inflammatory responses and JAK1/2 inhibition impairs the cytotoxic function of T cells in vitro,9- 11 the effects of aberrant JAK2 signaling and its modulation of T cells in patients with MF remain elusive.
A few recent studies showed increased T-cell response to neo-antigens in patients with myeloproliferative neoplasms.12-15 However, persistent tumor- induced activation prompts T cells to enter a dysfunctional state, referred to as T-
Myeloproliferative Disorders
Correspondence:
ZEEV ESTROV
zestrov@mdanderson.org
Received: February 6, 2020. Accepted: July 16, 2020. Pre-published: July 30, 2020.
https://doi.org/10.3324/haematol.2020.249441 ©2021 Ferrata Storti Foundation
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