Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD

Koehn, Brent H.; Saha, Asim; McDonald-Hyman, Cameron; Loschi, Michaël; Thangavelu, Govindarajan; Ma, Lie; Zaiken, Michael; Dysthe, Josh; Krepps, Walker; Panthera, Jamie; Hippen, Keli L.; Jameson, Stephen C.; Miller, Jeffrey S.; Cooper, Matthew A.; Farady, Christopher J.; Iwawaki, Takao; Ting, Jenny P.‐Y.; Serody, Jonathan S.; Murphy, William J.; Hill, Geoffrey R.; Murray, Peter J.; Bronte, Vincenzo; Munn, David H.; Zeiser, Robert; Blazar, Bruce R.

doi:10.1182/blood.2019001950

Cited by 57 publications

(55 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, MDSCs that are induced early after conditioning could rapidly differentiate and lose their immunosuppressive function after allogeneic HSCT. Indeed, pharmacologic agents that targeted Nlrp33 and the P2X7 receptor provided significantly higher survival, due to a lower incidence of GVHD (7,76).…”

Section: Discussion and Future Considerationsmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation

et al. 2020

View full text Add to dashboard Cite

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses. In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), MDSCs (in the donor graft and in the recipient, after allo-HSCT) might mediate immune suppression through multiple mechanisms. However, it remains unclear how MDSCs can be distinguished from their normal myeloid counterparts in the hematopoietic stem cell donor graft and during immune reconstitution after allo-HSCT in the recipient. Our ability to understand their exact role in allo-HSCT is limited by the absence of a specific gene signature or surface markers for identifying MDSCs among myeloid cells and by their plasticity in different microenvironments. According to various studies, MDSCs might induce transplant tolerance and control graft vs. host disease (GVHD), but their impact on the graft vs. tumor effect (GVT) is not fully understood. In fact, we know that MDSCs commonly expand in patients with cancer, and they are thought to promote hematological malignancy progression. However, little is known about whether depleting them might be an effective strategy for enhancing GVT effects. Here, we review data published over the past 40 years on allo-HSCT to delineate the different MDSC subsets, and their abilities to induce transplant tolerance and preserve the GVT effect. This review will provide a basis for determining whether one MDSC subset might be proposed as the most appropriate candidate for cellular therapies, due to its ability to modulate GVHD.

show abstract

Section: Discussion and Future Considerationsmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…To support this, allogeneic stem cell transplantation leads not only to a complete restore of the hematopoiesis, regression of BM fibrosis, and a progressive healing of the chronic inflammation. Although chronic inflammation in BM microenvironment can be present before a malignant clone develops, most likely it represents a consequence of presence of malignant clone [109][110][111]. It is no doubt that Nlrp3 inflammasome plays an important role in pathogenesis and progression of MPN, however more detailed studies are needed to better address its role in this disorders, as it has been done already in case of MDS [106,107].…”

Section: Myeloproliferative Neoplasms (Mps)mentioning

confidence: 99%

“…An important inducer of the Nlrp3 inflammasome in GvHD is activation of purinergic signaling by eATP [111][112][113]. After binding to the purinergic receptors P2X7 and P2X4, eATP induces activation of the Nlrp3 inflammasome [111]. However, this protein complex could also be activated by other DAMPs, cytokines, or active fragments of the ComC (C3a or C5a).…”

Section: The Nlrp3 Inflammasome In Gvhdmentioning

confidence: 99%

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

et al. 2020

View full text Add to dashboard Cite

Recent investigations indicate that hematopoiesis is coregulated by innate immunity signals and by pathways characteristic of the activation of innate immunity cells that also operate in normal hematopoietic stem progenitor cells (HSPCs). This should not be surprising because of the common developmental origin of these cells from a hemato/lymphopoietic stem cell. An important integrating factor is the Nlrp3 inflammasome, which has emerged as a major sensor of changes in body microenvironments, cell activation, and cell metabolic activity. It is currently the best-studied member of the inflammasome family expressed in hematopoietic and lymphopoietic cells, including also HSPCs. It is proposed as playing a role in (i) the development and expansion of HSPCs, (ii) their release from bone marrow (BM) into peripheral blood (PB) in stress situations and during pharmacological mobilization, (iii) their homing to BM after transplantation, and (iv) their aging and the regulation of hematopoietic cell metabolism. The Nlrp3 inflammasome is also involved in certain hematological pathologies, including (i) myelodysplastic syndrome, (ii) myeloproliferative neoplasms, (iii) leukemia, and (iv) graft-versus-host disease (GvHD) after transplantation. The aim of this review is to shed more light on this intriguing intracellular protein complex that has become a "rising star" in studies focused on both normal steady-state and pathological hematopoiesis.

show abstract

“…T regulatory (Treg) cells down-modulate T-cell activation through the production of immunosuppressive cytokines (TGFβ, IL-10), as well as through surface receptors (CTLA4), and can drastically impact both the anti-tumor immune response as well as the control of GvHD (57)(58)(59). Myeloid suppressive cells (60)(61)(62) and regulatory B cells (63)(64)(65) also play a potential role in attenuating the immune response and controlling effector cells and signaling mechanisms. Moreover, the presence of certain biomarkers may be predictive for the functioning of effector mechanisms; e.g., sorafenib-related IL-15 production causes an increase in CD8+CD107a+IFN-γ+ T cells with features of longevity and eliminates leukemia in secondary recipients, indicating that sorafenib after HCT might be more effective through induction of IL-15-mediated metabolic reprogramming of leukemia-reactive T cells (66).…”

Section: Monitoring Immune Cell Reconstitutionmentioning

confidence: 99%

Immune Monitoring After Allogeneic Hematopoietic Cell Transplantation: Toward Practical Guidelines and Standardization

2020

View full text Add to dashboard Cite

Hematopoietic cell transplantation (HCT) is often a last resort, but potentially curative treatment option for children suffering from hematological malignancies and a variety of non-malignant disorders, such as bone marrow failure, inborn metabolic disease or immune deficiencies. Although efficacy and safety of the HCT procedure has increased significantly over the last decades, the majority of the patients still suffer from severe acute toxicity, viral reactivation, acute or chronic graft-versus-host disease (GvHD) and/or, in case of malignant disease, relapses. Factors influencing HCT outcomes are numerous and versatile. For example, there is variation in the selected graft sources, type of infused cell subsets, cell doses, and the protocols used for conditioning, as well as immune suppression and treatment of adverse events. Moreover, recent pharmacokinetic studies show that medications used in the conditioning regimen (e.g., busulphan, fludarabine, anti-thymocyte globulin) should be dosed patient-specific to achieve optimal exposure in every individual patient. Due to this multitude of variables and site-specific policies/preferences, harmonization between HCT centers is still difficult to achieve. Literature shows that adequate immune recovery post-HCT limits both relapse and non-relapse mortality (death due to viral reactivations and GvHD). Monitoring immune parameters post-HCT may facilitate a timely prediction of outcome. The use of standardized assays to measure immune parameters would facilitate a fast comparison between different strategies tested in different centers or between different clinical trials. We here discuss immune cell markers that may contribute to clinical decision making and may be worth to standardize in multicenter collaborations for future trials.

show abstract

Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD

Abstract: These studies demonstrate how activation of the NLRP3 inflammasome pathway influences the function of myeloid-derived suppressor cells (MDSCs) in the setting of acute graft-versus-host disease (aGVHD).

Cited by 57 publications

References 80 publications

Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation

Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

Immune Monitoring After Allogeneic Hematopoietic Cell Transplantation: Toward Practical Guidelines and Standardization

Contact Info

Product

Resources

About