Therapeutic utility of immunosuppressive TREM2+ macrophages: an important step forward in potentiating the immune checkpoint inhibitors

Alkan, Fulya Koksalar; Korkaya, Hasan

doi:10.1038/s41392-020-00383-5

Cited by 5 publications

(2 citation statements)

References 5 publications

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“…28−30 However, the efficacy of PD-1 blockers is quite low (only 10−30%) due to the existence of multiple drug resistance mechanisms, and most patients cannot benefit from it. 31−34 As an important component of the tumor microenvironment (TME), M2-TAMs enhance tumor tolerance to anti-PD-1 therapy by overexpressing triggering receptor expressed on myeloid cells 2 (Trem2), 35,36 indoleamine 2,3-dioxygenase (IDO), and other molecules, 37−39 or by directly affecting the migration and infiltration of CD8 + T cells into tumors. 40−42 The repolarization of M2-TAMs is able to effectively enhance the efficacy of PD-1 blockers.…”

Section: Introductionmentioning

confidence: 99%

“…Immune checkpoint therapy aims to eliminate tumor cells by regulating the cytotoxic activity of T cells by co-suppression or co-stimulatory signals. − Anti-PD-1 immunotherapy, whether used alone or in combination with other molecular targeted therapies as first-line or second-line treatment, is in a leading position in the treatment of many malignancies owing to its long-lasting, broad spectrum efficacy, low toxicity, and other advantages. − However, the efficacy of PD-1 blockers is quite low (only 10–30%) due to the existence of multiple drug resistance mechanisms, and most patients cannot benefit from it. − As an important component of the tumor microenvironment (TME), M2-TAMs enhance tumor tolerance to anti-PD-1 therapy by overexpressing triggering receptor expressed on myeloid cells 2 (Trem2), , indoleamine 2,3-dioxygenase (IDO), and other molecules, − or by directly affecting the migration and infiltration of CD8 + T cells into tumors. − The repolarization of M2-TAMs is able to effectively enhance the efficacy of PD-1 blockers. , …”

Section: Introductionmentioning

confidence: 99%

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Dual Inhibition of Endoplasmic Reticulum Stress and Oxidation Stress Manipulates the Polarization of Macrophages under Hypoxia to Sensitize Immunotherapy

Jiang

Zhang

et al. 2021

ACS Nano

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M2-tumor associated macrophages (TAMs) play an important role in tumor genesis, progression, and metastasis, and repolarizing M2-TAMs to immune-promoting M1 type is increasingly recognized as a promising strategy against the clinically intractable carcinomas. It is observed that M2 macrophages have a high tropism to the tumor hypoxic area, with their endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway activated to inhibit cell glycolysis, promote oxidative phosphorylation (OXPHOS), and facilitate intracellular lipid accumulation, which in turn shapes the typical phenotypes of M2-TAMs, suggesting that manipulating the ER stress response of M2-TAMs might stand as a breakthrough for antitumor therapy. However, current attempts to repolarize M2 cells remain limited and are greatly challenged by the hypoxic nature of tumors. Also, the high level of reactive oxygen species (ROS) in the tumor microenvironment (TME) is favorable for the polarization of M2-TAMs. Here, we encapsulated KIRA6, an inhibitor of the IRE1-XBP1 pathway, into a reductive nanoemulsion containing α-tocopherol. Our α-T-K had dual inhibitory effects on the ER stress and oxidative stress. Both in vitro and in vivo experiments suggested that α-T-K effectively reprogrammed M2 macrophages even under hypoxia, achieved by increasing glycolysis and suppressing fatty acid oxidation (FAO). In addition, our data revealed that α-T-K not only delayed tumor growth but elevated the curative effect of PD-1 antibody. Our research demonstrated that simultaneous inhibition of ER stress and oxidative stress could effectively repolarize M2-TAMs under hypoxia, which not only filled the current gap in regulating the biological repolarization of macrophages under hypoxia but provided a meaningful reference for the clinical immunotherapy of sensitized anti-PD-1.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dual Inhibition of Endoplasmic Reticulum Stress and Oxidation Stress Manipulates the Polarization of Macrophages under Hypoxia to Sensitize Immunotherapy

Jiang

Zhang

et al. 2021

ACS Nano

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A single‐cell transcriptomic atlas of severe intrauterine adhesion

Xia,

Ye,

Zeng

et al. 2024

MedComm – Future Medicine

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Intrauterine adhesion (IUA) is a common endometrial disease caused by injury, leading to reproductive health issues. Current treatments have limited effectiveness, side effects, and high recurrence rates, especially, in severe cases. However, the underlying molecular and cellular mechanisms are largely unknown. Here we performed a comprehensive analysis by profiling integrated single‐cell transcriptomes of over 72,000 individual endometrial cells, encompassing samples from both patients with IUA and those with normal endometrium. We identified changes in cell type‐specific molecular signatures, including the inflammatory activation in immune cells, extensive damage in epithelial subpopulations, and the deposition of collagen secreted by fibroblasts subpopulations. Our results demonstrated activation of the TREM2+ macrophages, which displayed properties of inflammatory regulation. Annexin A1+ NK subpopulations exhibited the highest susceptibility among NK subtypes, displaying decreased cellular density and the most pronounced differential gene expression. Furthermore, we identified the matrix metallopeptidase 7 (MMP7+) and C‐C motif chemokine ligand 5 (CCL5+) unciliated epithelial subtype originated from pituitary tumor‐transforming gene 1 (PTTG1+) unciliated epithelium as the most vulnerable subpopulations to epithelial injury. Collectively, our study offers integrated resources of the cellular microenvironment of IUA, serving as a comprehensive cellular map of the disease in affected individuals. The insights gained from this study are expected to provide valuable resources for future diagnostic and therapeutic approaches.

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Clinical experience with CTLA-4 blockade for cancer immunotherapy: From the monospecific monoclonal antibody ipilimumab to probodies and bispecific molecules targeting the tumor microenvironment

Lisi

Lacal

Martire

et al. 2022

Pharmacological Research

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Therapeutic utility of immunosuppressive TREM2+ macrophages: an important step forward in potentiating the immune checkpoint inhibitors

Cited by 5 publications

References 5 publications

Dual Inhibition of Endoplasmic Reticulum Stress and Oxidation Stress Manipulates the Polarization of Macrophages under Hypoxia to Sensitize Immunotherapy

Dual Inhibition of Endoplasmic Reticulum Stress and Oxidation Stress Manipulates the Polarization of Macrophages under Hypoxia to Sensitize Immunotherapy

A single‐cell transcriptomic atlas of severe intrauterine adhesion

Clinical experience with CTLA-4 blockade for cancer immunotherapy: From the monospecific monoclonal antibody ipilimumab to probodies and bispecific molecules targeting the tumor microenvironment

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