Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity

Chen, Huiming; Touw, William van der; Wang, Yuan Shuo; Kang, Kyeongah; Mai, Sunny; Zhang, Jilu; Alsina‐Beauchamp, Dayanira; Duty, J. Andrew; Mungamuri, Sathish Kumar; Zhang, Bin; Moran, Thomas M.; Flavell, Richard A.; Aaronson, Stuart A.; Hu, Hong Ming; Arase, Hisashi; Ramanathan, Suresh Y.; Flores, Raja M.; Pan, Ping-Ying; Chen, Shu‐Hsia

doi:10.1172/jci97570

Cited by 160 publications

(145 citation statements)

References 75 publications

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“…Our group has also generated BAC-transgenic mice expressing LILRB2 for various studies. Recently we showed that αLILRB2 antibody therapy had a synergistic effect when combined with αPD-1 therapy to diminish tumor burden in a lung cancer model with BAC-transgenic LILRB2 mice, while simultaneously suppressing MDSC and T-reg infiltration into the tumor site ( 131 ).…”

Section: Methods To Prevent Myeloid Cell Contribution To Cancer Growtmentioning

confidence: 99%

“…Our group has shown that the murine homolog to LILRB2, PIRB, can regulate the entire network of suppressive functionality of myeloid cells, making the expression of LILRB2 an interesting therapeutic target ( 130 ). Additionally, we have shown that targeted therapy against LILRB2 on tumor-infiltrating myeloid cells can reverse their suppressive fate initiated by the malignancy and diminish lung cancer tumor burden in murine models ( 131 ).…”

Section: Tam/mdsc Identification Across Tumor Typesmentioning

confidence: 99%

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Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

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Tumor-mediated regulation of the host immune system involves an intricate signaling network that results in the tumor's inherent survival benefit. Myeloid cells are central in orchestrating the mechanisms by which tumors escape immune detection and continue their proliferative programming. Myeloid cell activation has historically been classified using a dichotomous system of classical (M1-like) and alternative (M2-like) states, defining general pro- and anti-inflammatory functions, respectively. Explosions in bioinformatics analyses have rapidly expanded the definitions of myeloid cell pro- and anti-inflammatory states with different combinations of tissue- and disease-specific phenotypic and functional markers. These new definitions have allowed researchers to target specific subsets of disease-propagating myeloid cells in order to modify or arrest the natural progression of the associated disease, especially in the context of tumor-immune interactions. Here, we discuss the myeloid cell contribution to solid tumor initiation and maintenance, and strategies to reprogram their phenotypic and functional fate, thereby disabling the network that benefits tumor survival.

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Section: Methods To Prevent Myeloid Cell Contribution To Cancer Growtmentioning

confidence: 99%

Section: Tam/mdsc Identification Across Tumor Typesmentioning

confidence: 99%

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

et al. 2020

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“…Upregulation of either LILRB1 or LILRB2 in macrophages was shown to provide an evasion mechanism for cancer cells against phagocytosis. Through activation of AKT and IL-4 signaling, LILRB2 antagonism induced a reduction in PD-L1 expression by macrophages and reprogramming of lung TAMs (44). CCR5 and ligands thereof (CCL3, CCL4, CCL5, CCL8, CCL11, and CCL13) were observed to follow the same pattern with a higher LR-score in immune and monocytic lineage infiltrated SDCs.…”

Section: Discussionmentioning

confidence: 85%

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities

Alame

Cornillot

Cacheux

et al. 2019

Preprint

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AbstractSalivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has been described rather exhaustively; yet, with respect to functional genomics and tumor microenvironment, little is known. In this study, transcriptomics and proteomics were combined to obtain the first characterization of the pathways deregulated in SDC. The data revealed the importance of Notch, TGB-β, and interferon-γ signaling. After associating computational biology, immunohistochemistry, multiplexed immunofluorescence, and digital imaging the first steps towards charting the cellular network within the microenvironment was initiated. According to immune infiltrate, two well-defined groups of tumors were observed, novel SDC immune checkpoints were discovered, and the key role played by macrophages and potentially NK cells in immunosuppression was shown. Furthermore, a clear trend between recurrence-free survival and M2 macrophage abundance was apparent. Independently, a measure of desmoplastic stromal reaction as determined by α-SMA abundance, was also shown. Altogether, these many findings open new perspectives for understanding and treating SDC. Before applying an immunotherapy, classical patient stratification according to immune infiltrate should be taken into account. Moreover, the microenvironment offers new potential targets including macrophages or NK cells, or even fibroblasts or hyaluronic acid. Related therapies that have been developed against, e.g., pancreatic tumors could inspire equivalent therapy for SDC.Additional informationFinancial support: MA (1 grant, GIRCI SOOM API-K 2016-811-DRC-AC), JC (2 grants, Fondation ARC PJA 20141201975, Labex EpiGenMed ANR 10-LABX-0012), AT (2 grants, Gunma University GIAR Research Program for Omics-Based Medical Science, Labex MabImprove ANR 10-LABX-0053 starting grant), ET (1 grant, SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553).No conflict of interest5408 words, 1 table, and 4 figuresStatement of translational relevanceBased on the presence or absence of an immune infiltrate, two groups of SDC were identified. These have the potential to provide a rationale for therapy and clinical trial enrolment. Two novel immune checkpoints that could be targeted were also identified; namely, CTLA-4/CD86 and TIM-3/galectin-9. Both showed the important contribution that macrophages and NK cells have in immunosuppression. Treatments that induce reprogramming or elimination of these cells could be considered. Moreover, the importance of the desmoplastic stroma was stressed. The stroma acts as a physical barrier against therapy suggesting that strategies developed against pancreatic tumors could inspire SDC treatments. For SDC devoid of immune infiltrate, components of the stroma including fibroblasts or hyaluronic acid could be targeted, e.g., in combination with drugs against immune checkpoints or mutated genes. Finally, evidence that Notch and TGF-β signaling are prevalent in SDC was obtained. This translates into additional therapeutic options.

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“…A recent study investigating the mode of action of Glatiramer acetate (Copaxone), a peptide-based drug licensed in the late 1990's, used to treat patients with the relapsing-remitting form of multiple sclerosis that ameliorates autoimmunity, identified LILRB2 and LILRB3 as potential ligands (55). On the other hand, blocking human LILRB2 with antagonistic mAb on human myeloid cells is able to promote their pro-inflammatory activity and enhance antitumor responses in preclinical models (56); and a LILRB2 mAb (MK-4830) recently entered phase I clinical trials (NCT03564691) for advanced solid tumors. Furthermore, recent data by Zhang and colleagues suggest that LILRB4 signaling in leukemia cells mediates T cell suppression and supports tumor cell dissemination to distal organs (57).…”

Section: Discussionmentioning

confidence: 99%

LILRB3 (ILT5) is a myeloid checkpoint on myeloid cells that elicits profound immununomodulation

Yeboah

Papagregoriou

Jones

et al. 2020

Preprint

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Despite advances in identifying the key immunoregulatory roles of the human leukocyte immunoglobulin (Ig)-like receptor (LILR) family members, the function of the inhibitory receptor LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAb) was generated. LILBR3-specific mAb bound to discrete epitopes in either Ig-like domain two or four. LILRB3 ligation on primary human monocytes by agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunoregulatory functions of LILRB3 and identify it as an important myeloid immune checkpoint receptor.

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Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity

Cited by 160 publications

References 75 publications

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities

LILRB3 (ILT5) is a myeloid checkpoint on myeloid cells that elicits profound immununomodulation

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