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REVIEW ARTICLE - CXCL8 in primary myelofibrosis neutrophils show higher CXCR1 expression compared to
cells in an activated state. Indeed, CXCR1 expression is down-regulated by increased concentrations of cytokines, such as TNF-α, or through the activation of TLR2 and TLR4. Like CXCR1, CXCR2 is a major chemokine receptor in regulating neutrophil mobility and appears to be more responsive to lower CXCL8 concentrations. Activation of CXCR2 tends to stimulate CXCL8 signaling through CXCR1 as it increases its expression. In contrast, activation of CXCR1 results in downregulation of CXCR2 surface expres- sion.45,84,88,89 In physiological circumstances, the release of maturated neutrophils from the BM is mediated by the activation of CXCR2, which antagonizes the effects of the CXCL12 (stromal cell-derived factor 1α [SDF-1α])/CXCR4 chemokine axis.90 Interaction between CXCR4 and its li- gand CXCL12 retains CXCR4 expressing cells within the BM niche. CXCR4 is down-regulated on mature neutrophils by cytokines, e.g., G-CSF. Similar to CXCR1, the expression of CXCR2 is influenced by the cellular state of activation, and stimulation of the cells with TNF-α results in downregula- tion of CXCR2. Nonetheless, it should be emphasized that altered receptor expression does not necessarily result in altered functional responses, and the opposite is also true.84,91,92 As mentioned earlier, another important note is that mice lack CXCL8, and that most of our knowledge on CXCR1/2 signaling pathways is derived from murine models. Therefore, extrapolation of murine experiments concerning CXCR1/2 biology to humans is difficult.45,48,63
In cancer biology, it is well known that CXCL8 plays a crucial role in the recruitment of neutrophils (tumor associated neutrophils [TAN]) to the tumor microenvironment. TAN show N1 or N2 phenotypes; N1 show anti-tumor activity through the release of inflammation-associated cytokines stimulating immune surveillance and local inflammation, whereas N2 show immunosuppressive and pro-angiogen- ic characteristics. N2 also stimulate remodeling of the extracellular matrix by the release of proteases. In solid malignancies, TAN attracted by CXCL8 are associated with poor clinical outcome and metastasis.93 MDS is character- ized by sustained elevation of CXCL8 concentrations, and neutrophils tend to show decreased migration capacities towards CXCL8 gradients.94,95 Moreover, as impaired mobility correlates with inferior prognosis, migration analysis of PB neutrophils was previously proposed as a prognostic tool within MDS.96 The functional and phenotypic characteristics of BM neutrophils in PMF are currently unknown.
Targeting the CXCL8-CXCR1/2 axis in primary myelofibrosis
As mentioned, dysregulated inflammatory signaling is a key feature in the pathophysiology of myeloproliferative disorders, and especially PMF. The exact effects of multi- ple elevated cytokines within MPN are far from completely
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understood. This review focuses on the role of CXCL8, as there is extensive interest in its role in oncogenesis due to its angiogenic and proinflammatory characteristics.93 In AML and MDS, inhibition of CXCR2 selectively inhibit- ed immature hematopoietic cell lines due to higher ex- pression of CXCR2 in CD34+ cells compared to healthy controls. Additionally, CXCL8 was identified as one of the few genes significantly over-expressed in different stem and progenitor subsets.94 Previously, researchers had al- ready expressed their interest in CXCL8 as a therapeutic target in PMF. Dunbar et al. showed that hematopoietic progenitor cells from patients with myelofibrosis carry an enriched CXCL8-CXCR2 pathway signature and exhibit in- creased proliferation after exposure to exogenous CXCL8.6 To date, multiple classes of CXCR1/2 inhibitors have been characterized. In PMF, most evidence has been gathered with the CXCR1/2 inhibitor reparixin, which is an R-ibupro- fen derivative. Treatment with reparixin in aged-matched GATA1low mice reduces BM fibrosis. In addition, GATA1low mice treated with reparixin express lower levels of TGF-b, whereas expression of CXCR1/2 remains unchanged and expression of GATA1 increases.97 Genetic deletion of Cxcr2 abrogates fibrosis and improves OS in the hMPLW515L fibro- sis mouse model. Interestingly, administration of reparixin to human myelofibrosis-derived megakaryocytes reduces levels of both CXCL8 and VEGF in vitro.6 In June 2023, a phase II clinical trial with reparixin in patients with PMF was initiated (clinicaltrials.gov 05835466). The estimated study completion date is in March 2026.98 Other classes of CXCR1/2 inhibitors include the diaryl urea class and boronic acid-containing molecules, such as danirixin and SX-682, respectively. Danirixin is CXCR2-selective, and was tested to reduce neutrophil activation and NET production in patients with chronic obstructive pulmonary disease (COPD), but appeared effective in only a subset of indi- viduals. Although these clinical trials with danirixin were stopped due to insufficient efficacy, the results suggest CXCR2-independent neutrophil activation was not neg- ligible in a subset of patients.99,100 SX-682 is an oral dual allosteric inhibitor and was recently successfully tested in patients with hypomethylating agent failure MDS as part of a phase I trial.101
Besides its receptors, CXCL8 itself may also be a therapeu- tic target. BMS-986253 (previously known as HuMax-IL8) is a humanized monoclonal antibody against CXCL8. CXCL8 became a therapeutic target in various cancers as it tends to promote the acquisition of mesenchymal features, im- mune escape, and the recruitment of protumoral immune cells, e.g., myeloid-derived suppressor cells to the tumor environment. Blocking CXCL8 prevented acquisition of mesenchymal features by tumor cells and reduced treat- ment resistance. Various clinical trials with BMS-986253 in combination with antibodies targeting programmed death-1 (PD-1)/cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in advanced tumors such as melanoma are
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