King’s Research Portal DOI: 10.1200/JCO.19.01823 Document Version Peer reviewed version Link to publication record in King's Research Portal Citation for published version (APA): Winter, S., Shoaie, S., Kordasti, S., & Platzbecker, U. (2020). Integrating the "Immunome" in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design: Systems immunology; a way forward in MDS. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(15), 1723-1735. [jco.19.01823]. https://doi.org/10.1200/JCO.19.01823 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. 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Sep. 2021 1 Journal of Clinical Oncology 2 Review Article 3 Integrating the ‘Immunome’ in the stratification of myelodysplastic syndromes 4 and future clinical trial design 5 Running title: Systems immunology; a way forward in MDS 6 Authors: Susann Winter1,3, Saeed Shoaie2, Shahram Kordasti‡3,4, Uwe Platzbecker5,6,7,3,4 7 Date of acceptance: 7th January 2020 8 Affiliations: 9 1 Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical 10 University Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden; and 11 German Cancer Research Center (DKFZ), Heidelberg, Germany 12 2 Centre for Host-Microbiome Interactions, Dental Institute, King’s College London, UK 13 3 Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College 14 London, UK 15 4 Haematology Department, Guy’s Hospital, London, UK 16 5 Medical Clinic and Policlinic 1, Haematology and Cellular Therapy, University of Leipzig 17 Medical Center, Germany 18 6 German MDS Study Group (G-MDS), Leipzig, Germany 19 7 German Cancer Consortium (DKTK); and German Cancer Research Center (DKFZ), Heidelberg, 20 Germany 21 ‡Correspondence to S.K., e-mail: [email protected], telephone: +44 (0) 20 7848 22 8028, address: Guy’s Hospital, St Thomas Street, London, SE1 9RT 1 23 Abstract 24 Myelodysplastic syndromes (MDS) are characterised by ineffective haematopoiesis and often 25 include a dysregulation and dysfunction of the immune system. In the context of population 26 ageing, MDS incidence is set to rise substantially, with exponential increases in health care 27 costs, given the limited and expensive treatment options for these patients. Treatment 28 selection is mainly based on calculated risk categories according to a Revised International 29 Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of 30 disease progression, it is an ineffective predictor of response to disease-modifying therapies. 31 Redressing these unmet needs, the ‘immunome’ is a key, multifaceted component in the 32 initiation and overall response against malignant cells in MDS, and the current omission of 33 immune status monitoring may in part explain the insufficiencies of current prognostic 34 stratification methods. Nevertheless, integrating these and other recent molecular advances 35 into clinical practice proves difficult. This review highlights the complexity of immune 36 dysregulation in MDS pathophysiology, and the fine balance between smouldering 37 inflammation, adaptive immunity, and somatic mutations in promoting or suppressing 38 malignant clones. We review the existing knowledge and discuss how state-of-the-art immune 39 monitoring strategies could potentially permit novel patient sub-stratification, thereby 40 empowering practical predictions of response to treatment in MDS. We propose novel 41 multicentre studies, which are needed to achieve this goal. 42 Keywords: MDS, immune dysregulation, immune profile, patient stratification 2 43 Introduction 44 Myelodysplastic syndromes (MDS) represent a group of acquired clonal disorders of 45 haematopoietic stem and progenitor cells (HSPCs), characterised by ineffective 46 haematopoiesis, peripheral cytopenias, genetic instability, and an increased risk of 47 progression to acute myeloid leukaemia (AML)1. Considering the higher prevalence in elderly 48 patients, the population ageing in developed countries as well as higher diagnostic awareness, 49 the incidence of MDS is set to rise substantially in coming decades2. 50 Clinical outcomes can vary greatly, even between patients considered to have the same MDS 51 subtype. Thus, MDS display marked heterogeneity regarding prognosis and the risk of disease 52 progression. To overcome this heterogeneity, the IPSS was introduced and then later revised 53 (IPSS-R) with the aim to provide discriminatory prognostic risk assessment regarding overall 54 survival and risk of progression to AML3. Whilst the IPSS-R reliably predicts the risk of disease 55 progression, it is not an effective tool to predict response to disease-modifying therapies4. 56 This is not surprising since the IPSS-R, like the original IPSS, was developed based on clinical 57 data from untreated MDS patients. Recent advances in targeted and large-scale next 58 generation sequencing (NGS) have helped to illuminate the dynamic genomic landscape in 59 MDS5–7. Although none of the most common recurrent somatic mutations is disease-defining, 60 some have an independent impact on overall survival, such as in TP538. Thus, addition of 61 molecular data to the IPSS-R can improve its predictive power5, 8, 9. 62 Recent advances have also highlighted the role of immune dysregulation in MDS pathogenesis 63 but are currently omitted from IPSS-R. This includes both abnormal activation of innate 64 immune pathways and associated inflammation as well as aberrant cellular immune 65 responses of independent prognostic value, which dynamically evolve during disease 3 66 progression10–13. The addition of comprehensive immunologic data to prognostic models 67 could, similar to mutational data, further help to refine risk stratification across the boundary 68 of lower- and higher-risk MDS. We envisage that continued clarification of the immune 69 pathways that are dysregulated in selected MDS subtypes will improve patient stratification, 70 the use and outcomes of existing treatments and novel immunotherapies, and drive the 71 development of new targeted drugs. In this review, we highlight recent advances in the 72 understanding of immune dysregulation in MDS, discuss their clinical implications as well as 73 potential therapeutic applications, and outline how immune profiling could be implemented 74 in future clinical trials. 75 Predisposing and potential driving immune factors 76 a) Smouldering inflammation and immunosenescence 77 Chronic inflammation due to long-lasting exposure to persistent infection or sterile 78 inflammation is a well-established predisposing factor for cancer14, 15, and increasing evidence 79 implicates the activation of innate immune signalling in age-related haematopoietic 80 senescence16, bone loss17, and MDS18. In fact, normal human ageing represents a state of 81 chronic low-grade sterile inflammation, similar to that originally described as ‘para- 82 inflammation’ by Medzhitov19, and commonly referred to as ‘inflammaging’20. Stressed, 83 damaged or otherwise malfunctioning, and/or dead cells release endogenous inducers of 84 sterile inflammation, including damage-associated molecular patterns (DAMPs) like high- 85 mobility-group-protein B1 (HMGB1) and alarmin S100 proteins, which can be sensed through 86 different receptors, such as Toll-like receptors (TLRs) and cytosolic nucleotide-binding domain 87 and leucine-rich repeat pattern recognition receptors (NLRs)19, 20. The physiological purpose 88 of the ensuing inflammatory response early in life and adulthood is to restore functionality 4 89 and homeostasis in the tissue. However, in old age, a period in life largely not foreseen by 90 evolution, the continuous exposure to inflammatory stimuli/stressors (the ‘immune 91 biography’) becomes detrimental, setting the biologic background favouring the susceptibility 92 to age-related inflammatory disorders, autoimmunity, and deterioration of haematopoiesis. 93 A reduced capacity to defend against pathogens and to initiate adaptive immunity is observed 94 in ageing humans, together with enhanced pro-inflammatory reactions fuelled by 95 ‘endogenous/self-molecular garbage’20, 21. The presence of ‘smouldering’ inflammation in the 96 elderly may aid