Integrating the "Immunome" in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design.

Susann Winter,Shahram Kordasti,Saeed Shoaie,Uwe Platzbecker

doi:10.1200/jco.19.01823

Abstract

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and often include a dysregulation and dysfunction of the immune system. In the context of population aging, MDS incidence is set to increase substantially, with exponential increases in health care costs, given the limited and expensive treatment options for these patients. Treatment selection is mainly based on calculated risk categories according to a Revised International Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of disease progression, it is an ineffective predictor of response to disease-modifying therapies. Redressing these unmet needs, the "immunome" is a key, multifaceted component in the initiation and overall response against malignant cells in MDS, and the current omission of immune status monitoring may in part explain the insufficiencies of current prognostic stratification methods. Nevertheless, integrating these and other recent molecular advances into clinical practice proves difficult. This review highlights the complexity of immune dysregulation in MDS pathophysiology and the fine balance between smoldering inflammation, adaptive immunity, and somatic mutations in promoting or suppressing malignant clones. We review the existing knowledge and discuss how state-of-the-art immune monitoring strategies could potentially permit novel patient substratification, thereby empowering practical predictions of response to treatment in MDS. We propose novel multicenter studies, which are needed to achieve this goal.

Highlights

Myelodysplastic syndromes (MDS) represent a group of acquired clonal disorders of hematopoietic stem and progenitor cells (HSPCs), characterized by ineffective hematopoiesis, peripheral cytopenias, genetic instability, and an increased risk of progression to acute myeloid leukemia (AML).[1]
TET2, SFRS2, ASXL1, DNMT3A, U2AF1) mutations aberrant lymphocytes on the adaptive immune response and MDS/AML pathogenesis.[33,41]
Recent studies point to the existence of shared autoinflammatory NLRP3-related pathways in clonal hematopoiesis of indeterminate potential (CHIP)/MDS and associated comorbidities,[44] and suggest NLRP3 as a shared genetic risk factor for MDS and paraneoplastic Sweet syndrome.[45]

Summary

INTRODUCTION

Myelodysplastic syndromes (MDS) represent a group of acquired clonal disorders of hematopoietic stem and progenitor cells (HSPCs), characterized by ineffective hematopoiesis, peripheral cytopenias, genetic instability, and an increased risk of progression to acute myeloid leukemia (AML).[1]. Increased levels of DAMPs (eg, S100A8/9) and activated NLR family, pyrin domain-containing protein 3 (NLRP3) inflammasomes are evident in MDS, lower-risk disease.[18,23,24,25] Notably, MDS HSPCs are susceptible to DAMPs because they overexpress TLRs26,27 along with signal transducers, such as IRAK128 and TRAF6.29 Ligation of S100A8/9 to TLR4 induces NFkB–mediated transcription of proinflammatory cytokines, including pro–interleukin (IL)-1b and IL-18, and transcriptional priming of inflammasome components.[30] Once activated, the NLRP3 inflammasome directs caspase1–dependent conversion of pro–IL-1b/IL-18 to their active forms and inflammatory pyroptotic cell death.[18] The consecutive release of proinflammatory cytokines, reactive oxygen species, and other intracellular contents into the extracellular milieu further activates the NLRP3 inflammasome, driving pyroptosis of HSPCs, consequent cytopenias, and an inflammatory circuit (Fig 1) This milieu may support the propagation of the MDS clone through various pathways, including Wnt/b-catenin signaling[31] or aberrant activation of the IL-1/p38MAPK pathway.[32] NLRP3 inflammasome activation seems to be licensed by S100A8/ 9 and MDS-related gene mutations and is evident in patients with del(5q) MDS, featuring activation of the p53S100A8/9-TLR4 axis.[10,18,24] whether inflammasome activation is a general feature of lower-risk MDS or particular subgroups needs to be evaluated in larger cohorts in the future.

Background mutation

Findings

CONCLUSION