Programmed Cell Death Receptor (PD-1) Ligand (PD-L1) expression in Philadelphia chromosome-negative myeloproliferative neoplasms

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A deeper understanding of the anti-cancer immune response and of the different immune regulatory mechanisms in patients with MPN has paved the way for an increased perception of the potential of cancer immunotherapy in MPN. Therapeutic vaccination targeting the driver mutations in MPN is one recently described potential new treatment modality. Furthermore, T cells can directly react against regulatory immune cells because they recognize proteins like arginase and programmed death ligand 1 (PD-L1). Therapeutic vaccination with arginase or PD-L1 therefore offers a novel way to directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens like mutant CALR and mutant JAK2. Other therapeutic options that could be used in concert with therapeutic cancer vaccines are immune checkpoint–blocking antibodies and interferon-α. For more advanced MPN, adoptive cellular therapy is a potential option that needs more preclinical investigation. In this review, we summarize current knowledge about the immune system in MPN and discuss the many opportunities for anti-cancer immunotherapy in patients with MPN.

Section: The Immune System In Mpnmentioning

confidence: 99%

Cancer Immune Therapy for Philadelphia Chromosome-Negative Chronic Myeloproliferative Neoplasms

Holmström

Hasselbalch

Andersen

2020

“…In addition, though the PD-1/PD-L1 axis has been a popular subject in cancer research, little has been done in MPN until very recently. Wang et al and Prestipino et al initiated the first studies on PD-1/PD-L1 in MPN, and their results show that this immune axis could be a relevant therapeutic target for MPN [ 124 , 128 ] because it seems to be triggered by key actors of the disease’s development (oncogenic driving mutations), and it is also involved in immune silencing.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Wang et al demonstrated that significantly higher levels of PD-1 and PD-L1 were found in MPN patients (including ET, PV, and MF) compared with controls [ 124 ]. Moreover, still in the context of MPN, PD-L1 has been found to be expressed more abundantly on the membranes of megakaryocytes and myeloid cells, including monocytes [ 125 ], whereas PD-1 expression was found only on immune T cells.…”

Section: Targeting the Pd-1/pd-l1 Axis In Mpnmentioning

confidence: 99%

“…Moreover, still in the context of MPN, PD-L1 has been found to be expressed more abundantly on the membranes of megakaryocytes and myeloid cells, including monocytes [ 125 ], whereas PD-1 expression was found only on immune T cells. One study in 63 MPN patients found a rise in PD-1 and PD-L1 expression at the surface of many cell types including CD4+, CD8+, CD14+, and CD34+ cells, regardless of the patient’s mutational status [ 124 ]. Another study reported that more than 50% of PD-1 or PD-L1 expression was associated with enhanced response to PD-1 inhibition treatment in solid tumors, and a higher percentage of PD-1 and PD-L1 was found in circulating CD34+ cells in blood samples from MPN patients than in samples from healthy donors [ 126 ].…”

Section: Targeting the Pd-1/pd-l1 Axis In Mpnmentioning

confidence: 99%

See 1 more Smart Citation

Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms

Almeida

Regimbeau

Jego

et al. 2020

Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy.

“…Accordingly, a phase 2 trial of selinexor in patients with MF refractory or intolerant to JAK inhibitors (ESSENTIAL) is underway (NCT03627403). The expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are increased in MPN cells [ 98 ], and immune checkpoint inhibition via antagonism of PD-1 by pembrolizumab has been demonstrated to enhance/restore mutant calreticulin-specific T-cell immunity [ 99 ]. Clinical studies of pembrolizumab (NCT03065400) and nivolumab (NCT02421354) have been conducted in patients with MF, and results are awaited.…”

Section: Other Novel Targets In Mfmentioning

confidence: 99%

Novel Concepts of Treatment for Patients with Myelofibrosis and Related Neoplasms

Bose

Masárová

Verstovšek

2020

Janus kinase (JAK) inhibition forms the cornerstone of the treatment of myelofibrosis (MF), and the JAK inhibitor ruxolitinib is often used as a second-line agent in patients with polycythemia vera (PV) who fail hydroxyurea (HU). In addition, ruxolitinib continues to be studied in patients with essential thrombocythemia (ET). The benefits of JAK inhibition in terms of splenomegaly and symptoms in patients with MF are undeniable, and ruxolitinib prolongs the survival of persons with higher risk MF. Despite this, however, “disease-modifying” effects of JAK inhibitors in MF, i.e., bone marrow fibrosis and mutant allele burden reduction, are limited. Similarly, in HU-resistant/intolerant PV, while ruxolitinib provides excellent control of the hematocrit, symptoms and splenomegaly, reduction in the rate of thromboembolic events has not been convincingly demonstrated. Furthermore, JAK inhibitors do not prevent disease evolution to MF or acute myeloid leukemia (AML). Frontline cytoreductive therapy for PV generally comprises HU and interferons, which have their own limitations. Numerous novel agents, representing diverse mechanisms of action, are in development for the treatment of these three classic myeloproliferative neoplasms (MPNs). JAK inhibitor-based combinations, all of which are currently under study for MF, have been covered elsewhere in this issue. In this article, we focus on agents that have been studied as monotherapy in patients with MF, generally after JAK inhibitor resistance/intolerance, as well as several novel compounds in development for PV/ET.