Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS

Trowbridge, Jennifer J.; Starczynowski, Daniel T.

doi:10.1084/jem.20201544

Cited by 127 publications

(80 citation statements)

References 133 publications

(167 reference statements)

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“…It is likely that increases in IFN-g come from expanded CD8 + T cells in MDS patients and contribute to disease progression through STAT1 activation (4,69). To further complicate the role of IFN-g, this cytokine was shown to promote MDS and AML differentiation into effector innate immune lineages (70)(71)(72). On a similar note, ET or PV patient derived erythroid colonies have increased IFN-g and STAT1 expression (73).…”

Section: Immunomodulating Interferonsmentioning

confidence: 99%

Inflammatory Cytokines Shape an Altered Immune Response During Myeloid Malignancies

2021

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The immune microenvironment is a critical driver and regulator of leukemic progression and hematological disease. Recent investigations have demonstrated that multiple immune components play a central role in regulating hematopoiesis, and dysfunction at the immune cell level significantly contributes to neoplastic disease. Immune cells are acutely sensitive to remodeling by leukemic inflammatory cytokine exposure. Importantly, immune cells are the principal cytokine producers in the hematopoietic system, representing an untapped frontier for clinical interventions. Due to a proinflammatory cytokine environment, dysregulation of immune cell states is a hallmark of hematological disease and neoplasia. Malignant immune adaptations have profound effects on leukemic blast proliferation, disease propagation, and drug-resistance. Conversely, targeting the immune landscape to restore hematopoietic function and limit leukemic expansion may have significant therapeutic value. Despite the fundamental role of the immune microenvironment during the initiation, progression, and treatment response of hematological disease, a detailed examination of how leukemic cytokines alter immune cells to permit, promote, or inhibit leukemia growth is lacking. Here we outline an immune-based model of leukemic transformation and highlight how the profound effect of immune alterations on the trajectory of malignancy. The focus of this review is to summarize current knowledge about the impacts of pro- and anti-inflammatory cytokines on immune cells subsets, their modes of action, and immunotherapeutic approaches with the potential to improve clinical outcomes for patients suffering from hematological myeloid malignancies.

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Section: Immunomodulating Interferonsmentioning

confidence: 99%

Inflammatory Cytokines Shape an Altered Immune Response During Myeloid Malignancies

2021

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“…Somatic mutations can be identified in the peripheral blood of healthy subjects, a phenomenon known as clonal hematopoiesis (CH) that reflects the expansion of mutated HSC; by years or decades, CH may evolve to AML, eventually involving clinically recognizable pre-leukemic syndromes, such as MDS or MPN (5)(6)(7)(8)(9)(10). In parallel, growing evidence also points to a prominent role of the immune system in shaping the evolution and clinical pictures of MN (11)(12)(13). The tumor immune microenvironment consists of multiple players, including adaptive and innate immune cells and stromal components, which may either antagonize or promote tumor progression; cancer cells themselves exhibit immunomodulatory properties and interact with microenvironmental components of the tumor niche (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

“…In parallel, growing evidence also points to a prominent role of the immune system in shaping the evolution and clinical pictures of MN (11)(12)(13). The tumor immune microenvironment consists of multiple players, including adaptive and innate immune cells and stromal components, which may either antagonize or promote tumor progression; cancer cells themselves exhibit immunomodulatory properties and interact with microenvironmental components of the tumor niche (11)(12)(13)(14). The connections between genetic evolution, changes in the immune microenvironment and clinical correlations, however, are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Technologies to Decipher the Immune Microenvironment in Myeloid Neoplasms: Perspectives and Opportunities

et al. 2022

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Myeloid neoplasms (MN) are heterogeneous clonal disorders arising from the expansion of hematopoietic stem and progenitor cells. In parallel with genetic and epigenetic dynamics, the immune system plays a critical role in modulating tumorigenesis, evolution and therapeutic resistance at the various stages of disease progression. Single-cell technologies represent powerful tools to assess the cellular composition of the complex tumor ecosystem and its immune environment, to dissect interactions between neoplastic and non-neoplastic components, and to decipher their functional heterogeneity and plasticity. In addition, recent progress in multi-omics approaches provide an unprecedented opportunity to study multiple molecular layers (DNA, RNA, proteins) at the level of single-cell or single cellular clones during disease evolution or in response to therapy. Applying single-cell technologies to MN holds the promise to uncover novel cell subsets or phenotypic states and highlight the connections between clonal evolution and immune escape, which is crucial to fully understand disease progression and therapeutic resistance. This review provides a perspective on the various opportunities and challenges in the field, focusing on key questions in MN research and discussing their translational value, particularly for the development of more efficient immunotherapies.

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“…Increasing evidence indicates that innate immune activation and excessive generation of inflammatory proteins, such as tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-6, alarmins, among others, both play a role in the pathophysiology of MDS. Chronic inflammation, as observed during aging, is also present in LR MDS [58]. Preclinical observations suggest that IL1/Toll-like receptor signaling and IRAK4 inhibition may improve hematopoiesis in murine MDFS models [59].…”

Section: Therapymentioning

confidence: 98%

Treatment of Lower Risk Myelodysplastic Syndromes

Santini

2022

Hemato

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Purpose of review: Management and Optimization of therapy for lower-risk myelodysplastic syndromes will be reviewed here. Recent findings: Lower-risk MDS typically present with clinical manifestations of anemia, which is the most frequently encountered cytopenia in this setting. While therapy with erythropoietic stimulating agents (ESAs) is used in the vast majority of cases, if correctly selected, some patients do not respond, or become irresponsive to ESAs. Novel agents with very different modes of action show promising clinical results in anemic LR-MDS refractory/relapsed after ESAs. Luspatercept, a TGFbeta family ligand trap, induces nearly 50% of transfusion independence in LR MDS. Another investigational agent showing efficacy and possibly disease modifying activity is the telomerase inhibitor imetelstat. Modulation of dose and schedule of hypomethylating agents, both injectable and oral, is currently being explored, and preliminary results are positive. There is still no standard therapeutic approach for thrombocytopenic and neutropenic LR MDS, although they do represent a smaller proportion of cases. Immunosuppressive treatments, as well as TPO mimetics, could represent a good option in selected MDS cases. Summary: At present, the availability of novel active agents allows the planning of sequential therapy, especially for anemic LR MDS. Better diagnosis and prognostic stratification may allow a more precise and personalized treatment.

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Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS

Cited by 127 publications

References 133 publications

Inflammatory Cytokines Shape an Altered Immune Response During Myeloid Malignancies

Inflammatory Cytokines Shape an Altered Immune Response During Myeloid Malignancies

Single-Cell Technologies to Decipher the Immune Microenvironment in Myeloid Neoplasms: Perspectives and Opportunities

Treatment of Lower Risk Myelodysplastic Syndromes

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