Autocrine <scp>VEGF</scp> signalling on M2 macrophages regulates <scp>PD</scp>‐L1 expression for immunomodulation of T cells

Lai, Yin‐Siew; Wahyuningtyas, Rika; Aui, Shin‐Peir; Chang, Ko‐Tung

doi:10.1111/jcmm.14027

Cited by 82 publications

(65 citation statements)

References 45 publications

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“…Previous studies also have shown that RON activation reduced the polarization of inflammatory M1 macrophages and induced the differentiation of immunosuppressive M2 macrophages. M2 macrophages promote PD-L1 expression through autocrine VEGF signaling(49,50). In our study, we demonstrate that high expression of both RON and PD-L1 (TIMC) is associated with poor overall survival in patients with CRC.…”

mentioning

confidence: 51%

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Liu¹,

Han²,

Shi³

et al. 2020

Preprint

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Background: PD-L1 immunotherapy remains poorly efficacious in colorectal cancer. The RON receptor tyrosine kinase plays an important role in regulating tumor immunity. Here, we identify patterns of RON and PD-L1 expression and explore the clinical significance of these patterns in colorectal cancer. Methods: Gene expression data were obtained from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) and were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor cells and the tumor microenvironment of colorectal cancer. Human colorectal cancer cell lines were treated with BMS-777607 to explore the relationship between RON activity and PD-L1 protein expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and western blot. Results: In the GEO cohort, cut-off values for RON and PD-L1 expression of 7.70 and 4.30, respectively, were determined. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 associated with poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and in tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON and high expression of PD-L1 in the tumor cell compartment was significantly correlated (p < 0.001). High expression of RON and PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with poor prognosis. In vitro , BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in colorectal cancer cells. Conclusions: RON, PD-L1 and the crosstalk between these proteins plays an important role in predicting the prognostic value of colorectal cancer. Moreover, phosphorylation of RON upregulates the expression of PD-L1, which provides a novel approach to immunotherapy in colorectal cancer.

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confidence: 51%

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Liu¹,

Han²,

Shi³

et al. 2020

Preprint

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“…Notably, both HGF and VEGF are reported to influence dendritic cell (DC) activity or maturation, upregulate the expression of PD-L1 and/ or PD-1, and stimulate immunosuppressive phenotypes in tumorassociated macrophages. [45][46][47][48]55,56 Moreover, anti-VEGF treatments have also been observed to reduce the numbers of Tregs and MDSCs in tumor-bearing mice. 46,57,58 Consistent with these previous observations, our data show significant decreases in the overall number of PD-L1-expressing cells by 19% and the numbers of Treg and M-MDSCs by 50% and 28% respectively in the tumor following AXT201 treatment.…”

Section: Discussionmentioning

confidence: 99%

“…25,[31][32][33] As such, the vascular normalization and growth factor inhibition effects of AXT201 suggested that the peptide be able to modulate the tumor immune response through regulation of the vasculature and signaling pathways. 29,[45][46][47][48] To further investigate the effects of AXT201 treatment on the TIME, we isolated 4T1 tumors after two weeks of treatment with AXT201 and used flow cytometry to assess changes in various lymphoid cell populations within the tumors induced by peptide treatment (flow cytometry gating strategies can be found in Figures S1). A summary of the findings can be found in Table 2.…”

Section: Axt201 Treatment Alters T Lymphocyte Cell Populations and Sementioning

confidence: 99%

Regulation of the tumor immune microenvironment and vascular normalization in TNBC murine models by a novel peptide

et al. 2020

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Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive disease with limited treatment options. Recently, the combination of the immune checkpoint inhibitor (ICI) atezolizumab (anti-PD-L1) with nab-paclitaxel was approved following a clinical trial that showed response rates in at least 43% of patients. While this approval marks a major advance in the treatment of TNBC it may be possible to improve the efficacy of ICI therapies through further modulation of the suppressive tumor immune microenvironment (TIME). Several factors may limit immune response in TNBC including aberrant growth factor signaling, such as VEGFR2 and cMet signaling, inefficient vascularization, poor delivery of drugs and immune cells, and the skewing of immune cell populations toward immunosuppressive phenotypes. Here we investigate the immune-modulating properties of AXT201, a novel 20 amino-acid integrin-binding peptide in two syngeneic mouse TNBC models: 4T1-BALB/c and NT4-FVB. AXT201 treatment improved survival in the NT4 model by 20% and inhibited the growth of 4T1 tumors by 47% over 22 days postinoculation. Subsequent immunohistochemical analyses of 4T1 tumors also showed a 53% reduction in vascular density and a 184% increase in pericyte coverage following peptide treatment. Flow cytometry analyses demonstrated evidence of a more favorable anti-tumor immune microenvironment following treatment with AXT201, including significant decreases in the populations of T regulatory cells, monocytic myeloid-derived suppressor cells, and PD-L1 expressing cells and increased expression of T cell functional markers. Together, these findings demonstrate immune-activating properties of AXT201 that could be developed in combination with other immunomodulatory agents in the treatment of TNBC.

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“…In addition to TGF-β, other immunosuppressive cytokines, such as vascular endothelial growth factor (VEGF), indolamine-pyrrole 2,3-dioxygenase (IDO) and IL10, act as immunosuppressive agents [105,106]. In other cases, macrophages with the M2 phenotype prevent the activation of T lymphocytes through the production of mediators such as IL-10 and prostaglandin E2 and promote tumor growth through the secretion of TGF-β and VEGF [107,108]. Alternatively, tumors may evade immune responses by taking advantage of PD-L1 macrophage expression that leads to T cell function suppression [109].…”

Section: Immune Checkpoints and Cancermentioning

confidence: 99%

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

Raimondo

Pucci

Alessandro

et al. 2020

IJMS

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The modulation of the immune system is one of the hallmarks of cancer. It is now widely described that cancer cells are able to evade the immune response and thus establish immune tolerance. The exploration of the mechanisms underlying this ability of cancer cells has always attracted the scientific community and is the basis for the development of new promising cancer therapies. Recent evidence has highlighted how extracellular vesicles (EVs) represent a mechanism by which cancer cells promote immune escape by inducing phenotypic changes on different immune cell populations. In this review, we will discuss the recent findings on the role of tumor-derived extracellular vesicles (TEVs) in regulating immune checkpoints, focusing on the PD-L1/PD-1 axis.

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Autocrine VEGF signalling on M2 macrophages regulates PD‐L1 expression for immunomodulation of T cells

Cited by 82 publications

References 45 publications

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

The pathological significance of abnormal RON and PD-L1 expression in colorectal cancer

Regulation of the tumor immune microenvironment and vascular normalization in TNBC murine models by a novel peptide

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

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