PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer

Sumitomo, Ryota; Hirai, Tatsuya; Fujita, Masaaki; Murakami, Hiroaki; Otake, Yosuke; Huang, Cheng‐Long

doi:10.1016/j.lungcan.2019.08.023

Cited by 76 publications

(60 citation statements)

References 41 publications

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“…PDL1 expressing M2-TAMs are signi cantly associated with increased immune evasion and more aggressive lung cancers. In addition, PDL1 has been reported as one of the targets of miR34a (48)(49)(50). Interestingly, consistent with the TCGA data, administration of LNA-antimiR-34a in BALB/C mice resulted in an increased Treg expansion in the bone marrow ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 79%

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Cheng

Mathew

et al. 2020

Preprint

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Background: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34a family is thought to play a role in tumor suppression, but the exact mechanism of action in HNSCC is not well understood. In addition, miR-34a is generally down-regulated HNSCC, but the role of chromosomal changes and mutation status on miR-34a expression remain unknown. Methods: Differential expression of miR-34a-3p, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, and rescue experiments. Lastly, mouse xenograft and locked nucleic acid anti-miRs were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo.Results: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. We found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Moreover, ectopic expression of miR-34a reduces HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells, myeloid cells, and regulatory T cells. Consistent with these findings, inhibition of miR-34a in an in vivo model of HNSCC leads to an increased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. Conclusions: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity, and could potentially represent a new therapeutic approach for HNSCC.

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Section: Resultssupporting

confidence: 79%

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Cheng

Mathew

et al. 2020

Preprint

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“…There are many inflammatory cells involved in the initiation, development, and metastasis of cancer, of which tumor-associated macrophages (TAMs) account for the largest proportion (50% of inflammatory cells) and play the most significant role [65,66]. Macrophages secrete a variety of cytokines and cytotoxic mediators, including activator of transcription 3 (STAT3), colonystimulating factor receptors (CSF-1), ROS, and MMP [67], which promote not only abnormal proliferation and apoptosis of early cells but also the formation and development of tumors and accelerate the infiltration and metastasis of tumor cells [68].…”

Section: Macrophages and Tumorsmentioning

confidence: 99%

“…Macrophages are the core participants in inflammation and the immune response and are involved in a variety of disease processes [65]. One of the most effective stimuli for macrophages is the bacterial endotoxin LPS [132].…”

Section: Effects Of β-Elemene On Macrophagesmentioning

confidence: 99%

“…Macrophages can be divided into two different phenotypes: the M1 phenotype, which is the classically activated phenotype that is involved in antitumor immunity, and the M2 phenotype, which is an alternatively activated phenotype with tumor-promoting properties [135]. A number of studies have found that TAMs are mostly M2-polarized, and it has been reported that these cells promote the growth and survival of tumors and may lead to resistance to cancer treatment [65]. β-Elemene not only decreases the proliferation, migration, and invasion and strengthens the radiosensitivity of lung cancer cells but also inhibits the promotion of migration, invasion, and EMT of lung cancer in M2 macrophageconditioned medium, regulating the polarization of macrophages from M2 to M1 [136].…”

Section: Effects Of β-Elemene On Macrophagesmentioning

confidence: 99%

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The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

Xie

Lei

et al. 2020

BioMed Research International

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Inflammatory mediators and inflammatory cells in the inflammatory microenvironment promote the transformation of normal cells to cancer cells in the early stage of cancer, promote the growth and development of cancer cells, and induce tumor immune escape. The monomeric active ingredient β-elemene is extracted from the traditional Chinese medicine Curcuma wenyujin and has been proven to have good anti-inflammatory and antitumor activities in clinical applications for more than 20 years in China. Recent studies have found that this traditional Chinese medicine plays a vital role in macrophage infiltration and M2 polarization, as well as in regulating immune disorders, and it even regulates the transcription factors NF-κB and STAT3 to alter inflammation, tumorigenesis, and development. In addition, β-elemene regulates not only different inflammatory factors (such as TNF-α, IFN, TGF-β, and IL-6/10) but also oxidative stress in vivo and in vitro. The excellent anti-inflammatory and antitumor effects of β-elemene and its ability to alter the inflammatory microenvironment of tumors have been gradually elaborated. Although the study of monomeric active ingredients in traditional Chinese medicines is insufficient in terms of quality and quantity, the pharmacological effects of more active ingredients of traditional Chinese medicines will be revealed after β-elemene.

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“…clinical studies have suggested that increased TaM density correlates with a poor prognosis in solid tumors (5,7,8) Several animal model experiments have validated this observation by demonstrating that increased TaM density is associated with tumor progression and metastasis, and overexpression of macrophage growth factors or chemokines (9,10). The deletion or re-differentiation of TaMs enhances immune cell-mediated anti-tumor responses and benefits from chemotherapy (11)(12)(13).…”

Section: Introductionmentioning

confidence: 97%

Tumor‑associated macrophages in lung cancer: Friendly or evil? (Review)

Wei

Tang

et al. 2020

Mol Med Rep

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Typically, tumor-associated macrophages (TaMs), an abundant population of leukocytes in lung cancer, are affected by tumor microenvironment (TMe) and shift towards either a pro-tumor (M2-like) or an anti-tumor phenotype (M1-like). M2-polarized macrophages, are one of the primary tumor-infiltrating immune cells and were reported to be associated with the promotion of cancer cell growth, invasion, metastasis, and angiogenesis. TaMs are considered a potential target for adjuvant anticancer therapies, and recent therapeutic approaches targeting the M2 polarization of TaMs have shown encouraging results. The present review discusses recent developments in the role of TaMs in cancer, in particular TaMs functions, clinical implication and prospective therapeutic strategies in lung cancer. Contents 1. introduction 2. Macrophage plasticity in lung cancer development 3. Functional aspects of macrophages in lung cancer 4. clinical implications of TaMs in lung cancer 5. TaM-targeted therapeutics 6. conclusions

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PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer

Cited by 76 publications

References 41 publications

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

Tumor‑associated macrophages in lung cancer: Friendly or evil? (Review)

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