The immune landscape in BCR-ABL negative myeloproliferative neoplasms: inflammation, infections and opportunities for immunotherapy

Abstract

Breakpoint cluster region-Abelson (BCR-ABL) negative myeloproliferative neoplasms (MPNs) are chronic myeloid neoplasms initiated by the acquisition of gene mutation(s) in a haematopoietic stem cell, leading to clonal expansion and over-production of blood cells and their progenitors. MPNs encompass a spectrum of disorders with overlapping but distinct molecular, laboratory and clinical features. This includes polycythaemia vera, essential thrombocythaemia and myelofibrosis. Dysregulation of the immune system is key to the pathology of MPNs, supporting clonal evolution, mediating symptoms and resulting in varying degrees of immunocompromise. Targeting immune dysfunction is an important treatment strategy. In the present review, we focus on the immune landscape in patients with MPNs - the role of inflammation in disease pathogenesis, susceptibility to infection and emerging strategies for therapeutic immune modulation. Further detailed work is required to delineate immune perturbation more precisely in MPNs to determine how and why vulnerability to infection differs between clinical subtypes and to better understand how inflammation results in a competitive advantage for the MPN clone. These studies may help shed light on new designs for disease-modifying therapies.

Keywords: Chronic myeloid malignancies; JAK inhibitors; immunity; immuno-oncology; immunocompromise.

Fig 1

Pro‐inflammatory interactions between clonal and non‐clonal cells. Inflammatory cytokines and growth factors such as TNFα, IL‐6, and IL‐8 confer a competitive advantage to the malignant MPN clone and are associated with increased symptom burden. JAK2 ^V617F mutations also alter the epigenetic regulation of TNF/NF‐κB inflammatory signalling pathways, further increasing inflammation. Extra‐cellular signals released by the MPN clone result in excess production of inflammatory cytokines by non‐clonal myeloid cells, lymphoid cells and bone marrow stroma. HSPCs, haematopoietic stem and progenitor cells; IL, interleukin; JAK2, Janus kinase 2; MPN, myeloproliferative neoplasm; NF‐κB, nuclear factor κ‐light‐chain‐enhancer of activated B cells; TGFβ, transforming growth factor beta; TNF, tumour necrosis factor.

Fig 2

Opportunities for immune‐based therapies in myeloproliferative neoplasm (MPN). (1) Identification of MPN neoantigens that elicit immune responses, such as JAK2 ^V617F and mutant CALR epitopes, and alternatively spliced proteins, such as eIF‐2α and protamine‐2 could be exploited for immune therapy; (2) Antibody therapies can be directed against cell surface proteins aberrantly expressed on the cell surface of MPN clone cells; (3) CAR‐T cells and adoptive T‐cell transfer confer T cells with the ability to target a specific protein, enhancing T‐cell recognition and destruction of mutant cells; (4) Blockade of the PD‐1 and CTLA‐4 inhibitory pathways on T cells enables better activation of naïve T cells by APCs such as dendritic cells, which present tumour antigens to the T cells for recognition. APC, antigen‐presenting cell; CALR, calreticulin; CAR, chimeric antigen receptor; CD, cluster of differentiation; CTLA‐4, cytotoxic T‐lymphocyte protein 4; eIF‐2α, eukaryotic initiation factor‐2α; IFN, interferon; JAK2, Janus kinase 2; MPN, myeloproliferative neoplasm; NF‐κB, nuclear factor κ‐light‐chain‐enhancer of activated B cells; PD‐1, programmed cell death‐protein 1; TNF, tumour necrosis factor.