Antigen presentation safeguards the integrity of the hematopoietic stem cell pool

Hernández-Malmierca, Pablo; Vonficht, Dominik; Schnell, Alexandra; Uckelmann, Hannah J.; Bollhagen, Alina; Mahmoud, Mohamed A. A.; Landua, Sophie-Luise; Salm, Elise van der; Trautmann, Christine L.; Raffel, Simon; Grünschläger, Florian; Lutz, Raphael; Ghosh, Michael; Renders, Simon; Correia, Nádia; Donato, Elisa; Dixon, Karin O.; Hirche, Christoph; Andresen, Carolin; Robens, Claudia; Werner, Paula; Boch, Tobias; Eisel, David; Osen, Wolfram; Pilz, Franziska; Przybylla, Adriana; Klein, Corinna; Buchholz, Frank; Milsom, Michael D.; Essers, Marieke; Eichmüller, Stefan B.; Hofmann, Wolf‐Karsten; Nowak, Daniel; Hübschmann, Daniel; Hundemer, Michael; Thiede, Christian; Bullinger, Lars; Müller‐Tidow, Carsten; Armstrong, Scott A.; Trumpp, Andreas; Kuchroo, Vijay K.; Haas, Simon

doi:10.1016/j.stem.2022.04.007

Cited by 50 publications

(33 citation statements)

References 95 publications

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“…Considering the widely reported expansion and mobilization of HSPCs across cancer models, it is also interesting to note that HSPCs express MHCII, co-stimulatory molecules (CD80, CD86) ( 26 , 27 ), and immune checkpoint receptors (PD-L1) ( 28 ), and can act as bona fide antigen presenting cells ( 29 ). While this suggests that the mobilized HSPCs enriched in the blood, lymphoid organs, and the tumor tissues of cancer patients may similarly engage in modulation of immune response, given their low numbers it is difficult to assess if such activity is biologically significant.…”

Section: Hematopoietic Stem and Progenitor Cells In Cancermentioning

confidence: 99%

Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

2022

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With the major advances in cancer immunology and immunotherapy, it is critical to consider that most immune cells are short-lived and need to be continuously replenished from hematopoietic stem and progenitor cells. Hematologic abnormalities are prevalent in cancer patients, and many ground-breaking studies over the past decade provide insights into their underlying cellular and molecular mechanisms. Such studies demonstrate that the dysfunction of hematopoiesis is more than a side-effect of cancer pathology, but an important systemic feature of cancer disease. Here we review these many advances, covering the cancer-associated phenotypes of hematopoietic stem and progenitor cells, the dysfunction of myelopoiesis and erythropoiesis, the importance of extramedullary hematopoiesis in cancer disease, and the developmental origins of tumor associated macrophages. We address the roles of many secreted mediators, signaling pathways, and transcriptional and epigenetic mechanisms that mediate such hematopoietic dysfunction. Furthermore, we discuss the important contribution of the hematopoietic dysfunction to cancer immunosuppression, the possible avenues for therapeutic intervention, and highlight the unanswered questions and directions for future work. Overall, hematopoietic dysfunction is established as an active component of the cancer disease mechanisms and an important target for therapeutic intervention.

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Section: Hematopoietic Stem and Progenitor Cells In Cancermentioning

confidence: 99%

Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

2022

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“…In addition, early observations that 1) STAT-4 –/– mice, which harbor predominately Th2 cells, have decreased numbers of cycling progenitors ( 21 ) and 2) that adoptive transfer of total CD4 + T cells into common gamma chain-deficient mice restored impaired myeloid differentiation indicated that CD4 + T cells regulate HSPC activity and basal hematopoiesis ( 20 ). These findings have been recently extended by Hernández-Malmierca and co-workers who demonstrated that the presentation of immunogenic antigens on MHC class II by HSPCs triggers an interaction with CD4 + T cells resulting in stem cell differentiation and depletion of immunogenic HSPCs ( 22 ).…”

Section: Regulatory T Cells In Hematopoiesismentioning

confidence: 70%

Regulation of hematopoietic and leukemia stem cells by regulatory T cells

Riether

2022

Front. Immunol.

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Adult bone marrow (BM) hematopoietic stem cells (HSCs) are maintained in a quiescent state and sustain the continuous production of all types of blood cells. HSCs reside in a specialized microenvironment the so-called HSC niche, which equally promotes HSC self-renewal and differentiation to ensure the integrity of the HSC pool throughout life and to replenish hematopoietic cells after acute injury, infection or anemia. The processes of HSC self-renewal and differentiation are tightly controlled and are in great part regulated through cellular interactions with classical (e.g. mesenchymal stromal cells) and non-classical niche cells (e.g. immune cells). In myeloid leukemia, some of these regulatory mechanisms that evolved to maintain HSCs, to protect them from exhaustion and immune destruction and to minimize the risk of malignant transformation are hijacked/disrupted by leukemia stem cells (LSCs), the malignant counterpart of HSCs, to promote disease progression as well as resistance to therapy and immune control. CD4+ regulatory T cells (Tregs) are substantially enriched in the BM compared to other secondary lymphoid organs and are crucially involved in the establishment of an immune privileged niche to maintain HSC quiescence and to protect HSC integrity. In leukemia, Tregs frequencies in the BM even increase. Studies in mice and humans identified the accumulation of Tregs as a major immune-regulatory mechanism. As cure of leukemia implies the elimination of LSCs, the understanding of these immune-regulatory processes may be of particular importance for the development of future treatments of leukemia as targeting major immune escape mechanisms which revolutionized the treatment of solid tumors such as the blockade of the inhibitory checkpoint receptor programmed cell death protein 1 (PD-1) seems less efficacious in the treatment of leukemia. This review will summarize recent findings on the mechanisms by which Tregs regulate stem cells and adaptive immune cells in the BM during homeostasis and in leukemia.

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“…Antigen presentation and immune cell proliferation in tumor microenvironment are crucial for the priming of anti-tumor immune response [22,23]. And, IGSF6 is restricted to immune system tissues [13,14].…”

Section: Igsf6 Expression Is Closely Related To Immune In Ltrates In ...mentioning

confidence: 99%

IGSF6 is a prognostic biomarker associated with the anti-tumor activity of macrophages in lung adenocarcinoma

Zheng

et al. 2022

Preprint

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Background Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily, and it is related to a variety of human diseases. However, the association of IGSF6 with the prognosis and anti-tumor immune response of lung adenocarcinoma (LUAD) remains unknown. Methods IGSF6 expression in pan-cancer and LUAD data of The Cancer Genome Atlas (TCGA) was analyzed by TIMER2.0 and GEPIA2, respectively. Quantitative-real-time-PCR (qRT-PCR), western-blot and immunohistochemistry (IHC) staining were performed to confirm the result of bioinformatics. IGSF6 expression level and promoter methylation level from major clinical features were analyzed by using UALCAN. Survival curves were used to assess the connection between IGSF6 expression and LUAD prognosis. The enrichment analysis was conducted by running the R software clusterProfiler package. TISIDB and Timer2.0 were utilized to investigate the association of IGSF6 with tumor infiltrating lymphocytes (TILs) in LUAD. Human Protein Atlas (HPA) and flow cytometry (FCM) were used to confirm IGSF6 localization in macrophages. Results IGSF6 expression was decreased in different types of cancers including LUAD. qRT-PCR, western-blot and IHC staining further confirmed this finding in paired tumor and normal tissues of LUAD patients. Meanwhile, promoter methylation level of IGSF6 in LUAD samples increased compared to that in peritumor samples, implying a potential mechanism that leads to the aberrant expression of IGSF6 in LUAD. By estimating the correlation between IGSF6 expression and the prognosis of LUAD, we found that low IGSF6 expression was significantly related to a worse survival rate. The enrichment analysis of IGSF6 co-expression showed that IGSF6 expression was closely associated with gene sets involved in immune cell proliferation and exogenous antigen presentation. In addition, high IGSF6 expression was positively correlated with immune infiltrates with anti-tumor activity, including M1 macropahges, dendritic cells (DCs), and T helper 1 (Th1) cells. Finally, IGSF6 was indicated to be mainly located on the membrane of macrophages in LUAD, which might enable exogenous antigen uptake and presentation so as to regulate immune response. Conclusions IGSF6 is a prognostic biomarker for LUAD, which may promote the anti-tumor immune response leading to ameliorative prognosis.

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Antigen presentation safeguards the integrity of the hematopoietic stem cell pool

Cited by 50 publications

References 95 publications

Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

Regulation of hematopoietic and leukemia stem cells by regulatory T cells

IGSF6 is a prognostic biomarker associated with the anti-tumor activity of macrophages in lung adenocarcinoma

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