Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti–PD-1 resistance

Ajith, Ashwin; Mamouni, Kenza; Horuzsko, Daniel D.; Musa, Abu; Dzutsev, Amiran K.; Fang, Jennifer R.; Chadli, Ahmed; Zhu, Xingguo; Lebedyeva, Iryna; Trinchieri, Giorgio; Horuzsko, Anatolij

doi:10.1172/jci167951

Cited by 10 publications

(2 citation statements)

References 88 publications

(134 reference statements)

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“…In many types of cancer, the overall prognosis is strongly tied to the amount and quality of neutrophils and macrophages in their microenvironment [203,204]. Therapeutically, the importance of these protumoral innate immune components provides targetable control points that can suppress tumorigenesis and ultimately cure patients of tumor burden [205][206][207][208]. In this part of the review article, we focus on mechanisms by which tumors recruit and retain those myeloid cells (Figure 4).…”

Section: Innate Immune Cell Migration To Cancermentioning

confidence: 99%

Immune Cell Migration to Cancer

Ryan,

Kim,

Lim

2024

Cells

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Immune cell migration is required for the development of an effective and robust immune response. This elegant process is regulated by both cellular and environmental factors, with variables such as immune cell state, anatomical location, and disease state that govern differences in migration patterns. In all cases, a major factor is the expression of cell surface receptors and their cognate ligands. Rapid adaptation to environmental conditions partly depends on intrinsic cellular immune factors that affect a cell’s ability to adjust to new environment. In this review, we discuss both myeloid and lymphoid cells and outline key determinants that govern immune cell migration, including molecules required for immune cell adhesion, modes of migration, chemotaxis, and specific chemokine signaling. Furthermore, we summarize tumor-specific elements that contribute to immune cell trafficking to cancer, while also exploring microenvironment factors that can alter these cellular dynamics within the tumor in both a pro and antitumor fashion. Specifically, we highlight the importance of the secretome in these later aspects. This review considers a myriad of factors that impact immune cell trajectory in cancer. We aim to highlight the immunotherapeutic targets that can be harnessed to achieve controlled immune trafficking to and within tumors.

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Section: Innate Immune Cell Migration To Cancermentioning

confidence: 99%

Immune Cell Migration to Cancer

Ryan,

Kim,

Lim

2024

Cells

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“…Several markers have been identified as the major regulators in MDSCs function, such as general control nonderepressible 2 (GCN2), 3 β2-adrenergic receptor 4 and the triggering receptor expressed on myeloid cell 1. 5 Previously, our group reported that G-protein-coupled receptor 84 (GPR84), a member of the G-protein coupled receptor (GPCR) superfamily, marks a subset of stronger immunosuppressive MDSCs than those lacking GPR84, and blocking GPR84 could enhance the anti-programmed cell death-1 (PD-1) therapy efficacy. 6 However, how GPR84 endows higher immunosuppression to MDSCs to suppress CD8 + T-cell antitumor response remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

MDSCs-derived GPR84 induces CD8⁺T-cell senescence via p53 activation to suppress the antitumor response

Liu,

Qin

et al. 2023

J Immunother Cancer

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BackgroundsG-protein-coupled receptor 84 (GPR84) marks a subset of myeloid-derived suppressor cells (MDSCs) with stronger immunosuppression in the tumor microenvironment. Yet, how GPR84 endowed the stronger inhibition of MDSCs to CD8+T cells function is not well established. In this study, we aimed to identify the underlying mechanism behind the immunosuppression of CD8+T cells by GPR84+MDSCs.MethodsThe role and underlying mechanism that MDSCs or exosomes (Exo) regulates the function of CD8+T cells were investigated using immunofluorescence, fluorescence activating cell sorter (FACS), quantitative real-time PCR, western blot, ELISA, Confocal, RNA-sequencing (RNA-seq), etc. In vivo efficacy and mechanistic studies were conducted with wild type, GPR84 and p53 knockout C57/BL6 mice.ResultsHere, we showed that the transfer of GPR84 from MDSCs to CD8+T cells via the Exo attenuated the antitumor response. This inhibitory effect was also observed in GPR84-overexpressed CD8+T cells, whereas depleting GPR84 elevated CD8+T cells proliferation and function in vitro and in vivo. RNA-seq analysis of CD8+T cells demonstrated the activation of the p53 signaling pathway in CD8+T cells treated with GPR84+MDSCs culture medium. While knockout p53 did not induce senescence in CD8+T cells treated with GPR84+MDSCs. The per cent of GPR84+CD8+T cells work as a negative indicator for patients’ prognosis and response to chemotherapy.ConclusionsThese data demonstrated that the transfer of GPR84 from MDSCs to CD8+T cells induces T-cell senescence via the p53 signaling pathway, which could explain the strong immunosuppression of GPR84 endowed to MDSCs.

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Pharmacological Inhibition or Silencing of TREM1 Restrains HCC Cell Metastasis by Inactivating TLR/PI3K/AKT Signaling

Ren,

Qiao,

Zhang

et al. 2024

Cell Biochem Biophys

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Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti–PD-1 resistance

Cited by 10 publications

References 88 publications

Immune Cell Migration to Cancer

Immune Cell Migration to Cancer

MDSCs-derived GPR84 induces CD8⁺T-cell senescence via p53 activation to suppress the antitumor response

Pharmacological Inhibition or Silencing of TREM1 Restrains HCC Cell Metastasis by Inactivating TLR/PI3K/AKT Signaling

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Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti–PD-1 resistance

Cited by 10 publications

References 88 publications

Immune Cell Migration to Cancer

Immune Cell Migration to Cancer

MDSCs-derived GPR84 induces CD8+T-cell senescence via p53 activation to suppress the antitumor response

Pharmacological Inhibition or Silencing of TREM1 Restrains HCC Cell Metastasis by Inactivating TLR/PI3K/AKT Signaling

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MDSCs-derived GPR84 induces CD8⁺T-cell senescence via p53 activation to suppress the antitumor response