CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis

Abstract

Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-kB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and the hMPLW515L murine model of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients.

Inflammation and bone marrow fibrosis: novel immunotherapeutic targets

“…Genetic deletion of Cxcr2 in mice alleviated the MF phenotype, reduced pro-inflammatory signaling and extended overall survival. Pharmacologic use of a CXCR1/2 antagonist, Reparixin, in two mouse models of MF [36 ▪ ,37 ▪ ], confirmed the beneficial effects of this therapeutic strategy [37 ▪ ,38].…”

“…Malignant HSCs and Mks from patients and fibrotic mice show higher expression of IL8/CXCL8, which is not mitigated by JAKi [19,36 ▪ ,37 ▪ ]. The expression of its receptors, CXCR1 and CXCR2, is also elevated in the disease, contributing, along with IL8/CXCL8, to the control of Mk proliferation [36 ▪ ]. Genetic deletion of Cxcr2 in mice alleviated the MF phenotype, reduced pro-inflammatory signaling and extended overall survival.…”

“…Increased serum levels of IL-8/CXCL8, a driver for neutrophil chemotaxis, have been associated with a negative prognosis in PMF patients [12]. Malignant HSCs and Mks from patients and fibrotic mice show higher expression of IL8/CXCL8, which is not mitigated by JAKi [19,36 ▪ ,37 ▪ ]. The expression of its receptors, CXCR1 and CXCR2, is also elevated in the disease, contributing, along with IL8/CXCL8, to the control of Mk proliferation [36 ▪ ].…”

SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms

“…17 IL-33, IL-6, TNFα, TGFβ, IL-13, and CXCL8/IL-8 have been identified as contributing to the pathogenesis of MPNs. [63][64][65][77][78][79][80][81][82][83][84][85][86][87][88][89] The addition of RMC-4550 to ruxolitinib in our studies drove the levels of TNFα, which contributes to clonal expansion in MPN models, 63 below those detected after vehicle and ruxolitinib monotherapy. While BET inhibition antagonizes MPN associated inflammatory signals via suppression of NFκB activity, 73 SHP2 has been implicated in positively regulating signaling by IL-1β, [90][91][92] IL-6, 93,94 CXCL8/IL-8, 95,96 as well as IL-13, 97 which has recently been implicated in driving myelofibrosis in MPN models.…”

GATA1-defective immune-megakaryocytes as possible drivers of idiopathic pulmonary fibrosis

“…At day 42, 72 or 78 from the beginning of the treatment, mice were euthanized, and their lung removed for histopathology observations. CXCR1/CXCR2 inhibitors : Sixteen eight-month-old Gata1 low mice were anesthetized with 2-to-3% isoflurane and implanted subcutaneously with an ALZET ® Osmotic Pump (model 2002) pre-filled with 200μL of vehicle (sterile saline) or the CXCR1/CXCR2 inhibitor Reparixin (7.5mg/h/Kg in sterile saline) as described 79, 80 . Mice were sacrificed 20 or 37 days after the beginning of the treatment, and their lungs removed for histopathological determinations.…”