Tumor Microenvironment Properties are Associated With Low CD68-positive Cell Infiltration and Favorable Disease-free Survival in EGFR-mutant Lung Adenocarcinoma

Gong, Zhihua; Chen, Junying; Cheng, Jianan; Sun, Chengdu; Jia, Qingzhu; Diao, Xinping; Zhu, Bo

doi:10.1016/j.cllc.2018.03.011

Cited by 9 publications

(12 citation statements)

References 26 publications

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“…Thus, in patients with NSCLC, the expression of CD68 in tumor tissue was significantly higher in comparison with normal tissue, and high amount of CD68+ macrophages positively correlated with a higher TNM stage, peritumoral LVD, and LN metastasis (56,165). Association between infiltration of CD68+ macrophages and EGFR-status was demonstrated in study of 105 surgically resected tumor samples (50 EGFR mutated and 55 EGFR wild-type) (171). CD68+ cells within the tumor niche exhibited more intensive infiltration in wild-type EGFR than in mutated tumors, and were related to lymph node invasion (171).…”

Section: Total Amount Of Tams In Lung Cancer Progressionmentioning

confidence: 99%

“…Association between infiltration of CD68+ macrophages and EGFR-status was demonstrated in study of 105 surgically resected tumor samples (50 EGFR mutated and 55 EGFR wild-type) (171). CD68+ cells within the tumor niche exhibited more intensive infiltration in wild-type EGFR than in mutated tumors, and were related to lymph node invasion (171).…”

Section: Total Amount Of Tams In Lung Cancer Progressionmentioning

confidence: 99%

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Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

et al. 2020

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Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth

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Section: Total Amount Of Tams In Lung Cancer Progressionmentioning

confidence: 99%

Section: Total Amount Of Tams In Lung Cancer Progressionmentioning

confidence: 99%

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

et al. 2020

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“…15 The ability to simultaneously quantify multiple cell types within a tissue specimen is critical for determining the function of immune infiltrates within a tumor, and may also improve our understanding of the mechanisms underlying different therapeutic responses and allow stratification of patients with different prognoses. 16,17 Previous studies that characterized transcription within the tumor immune microenvironment have used whole transcriptome sequencing data. 15,18,19 However, this method requires many fresh tumor specimens, which are not always available, and the cost is currently too high for routine use in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

<p>Transcriptional Characterization Of The Tumor Immune Microenvironment And Its Prognostic Value For Locally Advanced Lung Adenocarcinoma In A Chinese Population</p>

Chen¹,

Chen²,

Mao³

et al. 2019

CMAR

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Objective: We investigated the relationship of the transcriptional tumor immune microenvironment with prognosis of patients with locally advanced lung adenocarcinoma (LUAD). Materials and methods: A targeted RNA-Seq approach was used to measure the abundance of 395 immune-related transcripts of 24 formalin-fixed paraffin embedded (FFPE) tumor specimens from our institution and transcription data of 85 matched LUAD samples from The Cancer Genome Atlas (TCGA). Gene set variation analysis (GSVA) was used to identify gene sets related to prognosis, and the microenvironment cell-population (MCP)counter method was used to quantify infiltrated immune cells. Survival analysis with the log rank test was used to determine the relationships of different immune-related transcripts with prognosis. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Results: Among our patients, GSVA and the log rank test demonstrated that enrichment of the antigen processing pathway (P = 0.01) correlated with a favorable prognosis. MCP-counter and survival analysis demonstrated that greater CD8 T cell infiltration correlated with a favorable prognosis (P = 0.05), but greater infiltration of neutrophils (P = 0.014) and NK cells (P = 0.015) correlated with poor prognoses. Cox hazard analysis showed that greater infiltration of neutrophils was an independent risk factor for poor prognosis. These results were consistent with LUAD data from TCGA. Conclusion: When integrated with computational bioinformatics methods, targeted RNA-Seq from FFPE specimens provides profiles of the tumor immune microenvironment that have prognostic value for patients with locally advanced LUAD.

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“…PD-1/PD-L1 axis may not be the main immune escape route in EGFR mutant lung cancer. EGFR activation is likely responsible for the unin amed TME of this type tumor and participates in immunosuppression and immune escape [10,[17][18]. Therefore, better understanding the TME and exploring immune-related prognostic biomarkers will help to reveal the molecular mechanism, identify at-risk groups of patients and improve the clinical outcome as well.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the immunosuppressive TME may result from the absence of CD8+ T cell in ltrates and substantial reduction of TMB [9][10]16]. Emerging evidence demonstrates that EGFR mutations in NSCLC could affect a number of immune-related genes and induce an immunosuppressive TME [10,[17][18]. Hence, it is of great importance to explore immune-related prognostic genes for identifying at-risk patients and revealing the status of the immunosuppressive TME.…”

Section: Introductionmentioning

confidence: 99%

Identification of a gene signature closely related to immunosuppressive tumor microenvironment predicting prognosis of patients in EGFR mutant lung adenocarcinoma

Zhang

et al. 2020

Preprint

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Background: Lung adenocarcinomas (LUAD) harboring epidermal growth factor receptor (EGFR) mutations generally are unable to benefit from immune checkpoint inhibitors (ICIs), due to an immunosuppressive tumor microenvironment (TME) and a lower tumor mutation burden (TMB). Currently, there has been no gene signature that can comprehensively evaluate the TME and predict the prognosis of EGFR mutant LUAD patients. Methods: Using the cancer genome atlas (TCGA) database of EGFR mutant LUAD based on the immune score derived from the ESTIMATE algorithm, we screened the differential immune-related genes with prognostic value and compared the TMB profiles. Gene ontology (GO) and Kyoto encyclopedia of gene and genomic (KEGG) enrichment analysis were used to analyze the potential functions. The least absolute shrinkage and selectionator operator (LASSO) cox regression model was applied to identify a gene signature and constructed risk model. Kaplan-Meier survival and receiver operating characteristic (ROC) analysis were used to evaluate the prognostic value of the gene signature. CIBERSORT was used to evaluate the abundance of immune cells infiltration.Results: We screened 396 the differential immune-related genes based on immune score, whose potential functions were significantly related to T cell differentiation, immune response, cell cycle and cell proliferation. The disparities of TMB profile could be found between the high and low immune score group. Then, we identified a three-gene signature, including B and T lymphocyte attenuator (BTLA), BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) and centromere protein E (CENPE). The three-gene signature could well identify at-risk patients of EGFR-mutant LUAD patients in the training and validating set, and the high-risk patients were related to shorter overall survival (OS) (p=0.0053 and p=0.035). The immune activity of B cells and macrophages were higher in the low-risk group, in contrast the immune activity of Natural Killer (NK) cells and T cells were higher in the high-risk group. Conclusions: The three-gene signature closely related to immunosuppressive TME could predict risk prognosis of patients in EGFR mutant LUAD.

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Tumor Microenvironment Properties are Associated With Low CD68-positive Cell Infiltration and Favorable Disease-free Survival in EGFR-mutant Lung Adenocarcinoma

Cited by 9 publications

References 26 publications

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

<p>Transcriptional Characterization Of The Tumor Immune Microenvironment And Its Prognostic Value For Locally Advanced Lung Adenocarcinoma In A Chinese Population</p>

Identification of a gene signature closely related to immunosuppressive tumor microenvironment predicting prognosis of patients in EGFR mutant lung adenocarcinoma

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