Redirecting macrophage function to sustain their “defender” antitumor activity

Tzetzo, Stephanie; Abrams, Scott I.

doi:10.1016/j.ccell.2021.03.002

Cited by 18 publications

(20 citation statements)

References 15 publications

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“…In addition, they may repress T cell function via secretion of regulatory cytokines such as interleukin-10 (IL-10) and transforming growth factor b (TGF-b) (DeNardo and Ruffell, 2019;Noy and Pollard, 2014;Ruffell et al, 2014;Speiser et al, 2016). It is demonstrated that tumor-associated macrophages (TAMs) are plastic and able to switch their function in response to environmental cues in the TME (Amit et al, 2016;Tzetzo and Abrams, 2021), resulting in functional heterogeneity with diverse phenotypes. Nevertheless, the functional phenotypes of macrophage subpopulations remain unclear and the underlying mechanism whereby macrophages govern T cell fate is not completely understood.…”

Section: Introductionmentioning

confidence: 99%

The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth

et al. 2021

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Section: Introductionmentioning

confidence: 99%

The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth

et al. 2021

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“…Currently, it is evident that MDSCs are crucial regulators of tumor immunity and cancer progression ( Kramer and Abrams, 2020 ; Strauss et al, 2021 ; Veglia et al, 2018 ; Wu et al, 2020b ). Restraining or redirecting the process of myeloid cell generation is emerging as a promising novel strategy for immunotherapy ( Kaczanowska et al, 2021 ; Lin et al, 2021 ; Tzetzo and Abrams, 2021 ; Yu et al, 2021 ). These therapies could target the driving events in the following two partially overlapping phases: (1) the expansion and preconditioning of precursors and (2) the pathological activation of immature myeloid cells ( Condamine et al, 2015 ; Veglia et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…These cells represent a heterogeneous group of monocytic (M-MDSCs) and polymorphonuclear (PMN-MDSCs) precursors that universally regulate antitumor immunity and promote disease progression in cancers ( Cui et al, 2013 ; Mantovani et al, 2021 ; Olingy et al, 2019 ; Strauss et al, 2021 ). Reprogramming immunosuppressive MDSCs toward cells with antitumor function is an emerging notion that has attracted intense investigation ( Alicea-Torres et al, 2021 ; Bauer et al, 2018 ; Fujita et al, 2011 ; Tzetzo and Abrams, 2021 ; Veglia et al, 2019 ; Zhang et al, 2019 ). However, the pursuit of this goal is hampered by the limited understanding of the MDSC ontogeny and the precise regulatory mechanism ( Bronte and Pittet, 2013 ; Mohamed et al, 2018 ; Veglia et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen

Liu

Luo

et al. 2022

Journal of Experimental Medicine

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The spleen is an important site of hematopoietic stem/progenitor cell (HSPC) preconditioning and tumor-promoting myeloid cell generation in cancer, but the regulatory mechanism remains unclear. Here, we found that PKR-like endoplasmic reticulum kinase (PERK) mediated HSPC reprogramming into committed MDSC precursors in the spleen via PERK–ATF4–C/EBPβ signaling. Pharmacological and genetic inhibition of this pathway in murine and human HSPCs prevented their myeloid descendant cells from becoming MDSCs even with subsequent exposure to tumor microenvironment (TME) factors. In mice, the selective delivery of PERK antagonists to the spleen was not only sufficient but more effective than the tumor-targeted strategy in preventing MDSC activation in the tumor, leading to profound TME reshaping and tumor regression. Clinically, HSPCs in the spleen of cancer patients exhibit increased PERK signaling correlated with enhanced myelopoiesis. Our findings indicate that PERK-mediated HSPC preconditioning plays a crucial role in MDSC generation, suggesting novel spleen-targeting therapeutic opportunities for restraining the tumor-promoting myeloid response at its source.

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“…Multiple studies [ 8 – 10 ], including our previous studies [ 11 , 12 ], have shown that TAMs, including TAMs of the peripheral origin or microglial origin in the brain, are enriched in the glioma microenvironment and promote glioma progression. Recent studies have suggested that macrophage-targeted therapy is a novel and attractive approach for treating malignant tumors [ 13 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression

et al. 2022

Oncogene

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Exosomes can selectively secrete harmful metabolic substances from cells to maintain cellular homeostasis, and complex crosstalk occurs between exosomes and tumor-associated macrophages (TAMs) in the glioma immune microenvironment. However, the precise mechanisms by which these exosome-encapsulated cargos create an immunosuppressive microenvironment remain unclear. Herein, we investigated the effect of glioma-derived exosomes (GDEs) on macrophage polarization and glioma progression. We performed sequencing analysis of cerebrospinal fluid (CSF) and tumor tissues from glioma patients to identify functional microRNAs (miRNAs). High levels of miR-3591-3p were found in CSF and GDEs but not in normal brain tissue or glial cells. Functionally, GDEs and miR-3591-3p significantly induced M2 macrophage polarization and increased the secretion of IL10 and TGFβ1, which in turn promoted glioma invasion and migration. Moreover, miR-3591-3p overexpression in glioma cell lines resulted in G2/M arrest and markedly increased apoptosis. Mechanistically, miR-3591-3p can directly target CBLB and MAPK1 in macrophages and glioma cells, respectively, and further activate the JAK2/PI3K/AKT/mTOR, JAK2/STAT3, and MAPK signaling pathways. In vivo experiments confirmed that macrophages lentivirally transduced with miR-3591-3p can significantly promote glioma progression. Thus, our study demonstrates that tumor-suppressive miR-3591-3p in glioma cells can be secreted via exosomes and target TAMs to induce the formation of an immunosuppressive microenvironment. Collectively, these findings provide new insights into the role of glioma exosomal miRNAs in mediating the establishment of an immunosuppressive tumor microenvironment and show that miR-3591-3p may be a valuable biomarker and that blocking the encapsulation of miR-3591-3p into exosomes may become a novel immunotherapeutic strategy for glioma.

show abstract

Redirecting macrophage function to sustain their “defender” antitumor activity

Cited by 18 publications

References 15 publications

The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth

The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth

PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen

Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression

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