Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment

e15258 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, showed clinical benefit for patients (pts) with NSCLC alone (NCT02407990, CTR20160872) and in combination with chemotherapy (NCT03432598). Gene expression profiles (GEP) associated with response and resistance to tislelizumab in these studies were assessed. Methods: The GEP of baseline tumor samples from 59 nonsquamous (NSQ) and 42 squamous (SQ) NSCLC pts treated with tislelizumab monotherapy (mono) as ≥1L treatment, and 16 NSQ and 21 SQ pts treated with tislelizumab plus chemotherapy (combo) as 1L treatment were assessed using the 1392-gene HTG GEP EdgeSeq panel. NSQ and SQ cohorts were analyzed separately due to distinct GEP features shown by PCA and t-SNE clustering. Results: Tislelizumab mono and combo showed antitumor activity in NSCLC (Table). In 80 biomarker-evaluable samples, inflamed tumor signatures (inflammatory GEP; antigen presentation GEP) were associated with longer overall survival (log-rank test, NSQ mono: P=0.04, 0.003; NSQ combo: P=0.05, 0.02; SQ combo: P=0.06, 0.06). Monotherapy non-responders (NRs) were clustered into 2 subgroups (NR1, NR2) with distinct GEPs. Compared with responders, NR1 had proliferation signatures (elevated cell cycle [CC] and DNA repair) in both NSQ ( P=0.2, 0.02) and SQ ( P=0.03, 0.4) cohorts, trending toward low inflamed tumor signatures. In NR pts receiving combo, CC and DNA repair signatures were not enriched, and high CC and DNA repair scores were observed in some SQ combo responders versus NRs ( P=0.2, 0.02). NR2 had higher M2 macrophage and Treg cell signatures versus responders in both NSQ and SQ mono, despite high inflamed tumor and low proliferation signatures. NR2 also had increased expression of genes related to immune regulation and angiogenesis, including PIK3CD, CCR2, CD244, IRAK3, and MAP4K1 ( P<0.05) in NSQ, and PIK3CD, CCR2, CD40, CD163, MMP12, VEGFC, and TEK ( P<0.05) in SQ. Conclusions: Clinical benefit in pts with NSCLC receiving tislelizumab (mono or combo) was associated with high inflamed tumor signatures, while elevated immune suppressive cell signatures may indicate resistance. High proliferation signatures were associated with resistance to monotherapy, but not to combination therapy. Both immune- and tumor-intrinsic factors may be considered for validation in future clinical trials. [Table: see text]

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Possibility of tuning the differentiation state of tumor associated macrophages towards tumor controlling phenotypes

10.7287/peerj.preprints.27747v1 ◽

2019 ◽

Author(s):

Wenfa Ng

Keyword(s):

Gene Expression ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Immune Cells ◽

Cellular Differentiation ◽

Expression Patterns ◽

Gene Cassette ◽

Gene Expression Patterns ◽

M2 Macrophages ◽

M1 And M2 Macrophages

Although various immune cells could infiltrate the cellular and tissue environment surrounding a tumor, the tumor microenvironment nevertheless presents immunosuppressive conditions unfavorable for immune cells to conduct large scale attack on cancer cells. For example, T-cells that make it to the tumor microenvironment are typically non-functional in containing tumor growth. On the other hand, macrophages could infiltrate the tumor microenvironment and is an important cell type modulated by and which also modulates the tumor. Specifically, two variants of macrophages with different phenotypes are known to exhibit close interactions with tumors. Known as M1 and M2 macrophages, they present dichotomously different signals to the tumor. Specifically, M1 macrophages control tumor growth while M2 macrophages promote tumor growth. Thus, from a treatment perspective, it would be desirable to tune the phenotypes and cell differentiation program of macrophages towards the M1 subset. To do that, differential gene expression of macrophages in the M1 and M2 lineages must be understood. Such a goal could be achieved with the profiling of tumor associated macrophages from tumor biopsy samples for gene expression patterns characteristic of the two dominant macrophage lineages. Single cell RNA-sequencing conducted after flow cytometry sorting of M1 and M2 macrophages would highlight gene expression patterns associated with each lineage, and the cellular differentiation programs that prompted entry into particular macrophage subtype. Knowledge of gene expression pattern associated with each macrophage lineage is not useful for tuning their differentiation state unless specific transcription factor that trigger the regulon could be identified. To this end, transcription factors that have been upregulated in the differentiation program could be profiled from the transcriptome data, and help inform the design of vectors for targeted overexpression of specific transcription factor for modulating cellular differentiation of macrophage. Given their low immunogenicity, adeno-associated virus (AAV) could serve as vectors for ferrying the gene cassette containing specific transcription factors into macrophages. Delivery methods for the AAV could be via targeted local infusion of vectors to tumors or through the systemic circulation, but the latter approach would result in lower transfection efficiency. Collectively, possibility exists of tuning the differentiation state of macrophage associated with tumors for enabling tumor controlling lineage to be dominant. Such immuno-targeted therapy would harness the body’s macrophages for controlling tumor growth and represents a treatment option that may yield fewer side effects compared to conventional chemotherapy. But, identification of genes that control lineage-specific differentiation program and the delivery of gene cassette to macrophages for modulating their differentiation remain key challenges.

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High expression of suppressor of cytokine signaling 1 (SOCS1) associates with favourable responsiveness to neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma

10.21203/rs.3.rs-464237/v1 ◽

2021 ◽

Author(s):

Kai Xiong ◽

Yunfei Ye ◽

Jian Li ◽

Lin Lei ◽

He Xiao ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Microenvironment ◽

Esophageal Squamous Cell Carcinoma ◽

Neoadjuvant Therapy ◽

High Expression ◽

Cytokine Signaling ◽

Functional Genes ◽

M2 Macrophage ◽

M2 Macrophages ◽

Suppressor Of Cytokine Signaling

Abstract Background: The responsiveness to preoperative neoadjuvant therapy in esophageal squamous cell carcinoma (ESCC) is significantly related to the surgical effect and long-term prognosis of patients. Biomarkers for predicting the effect of preoperative neoadjuvant therapy of ESCC are urgently needed in clinical practice. M2 macrophage in the tumor microenvironment (TME) has been confirmed to have a definite correlation with neoadjuvant therapy. However, the research on the potential functional genes of M2 macrophage has not been carried out. The purpose of this study is to systematically screen the potential functional genes of M2 macrophages and verify the correlation between the expression of screened genes and responsiveness to neoadjuvant therapy in ESCC.Methods: The Cancer Genome Atlas (TCGA) database was used to screen the potential functional genes of M2 macrophages systematically. The correlation between the screened genes and responsiveness to neoadjuvant therapy in ESCC was analyzed in the training set GSE45670 and the validation set GSE104958. The correlation of the screened genes was confirmed in a cohort of 27 patients using immunohistochemistry (IHC).Results: A total of 11 M2 macrophage potential functional genes were screened out. The suppressor of cytokine signaling 1 (SOCS1) and ORAI calcium release-activated calcium modulator 3 (ORAI3) were selected for subsequent verification. The expression of SOCS1 and ORAI3 in 27 cases of ESCC was evaluated by the H-score system. The result showed that the high expression of SOCS1 was significantly correlated with favourable responsiveness to preoperative neoadjuvant therapy (AUC = 0.830, 95% CI: 0.647-1, P = 0.006). No significant correlation was found between the expression of ORAI3 and neoadjuvant therapy in ESCC (AUC=0.688, 95% CI: 0.478-0.899, P=0.117).Conclusion: The high expression of SOCS1 in the local tumor microenvironment is significantly correlated with favourable responsiveness to neoadjuvant therapy in patients with ESCC, which can be used as a biomarker to predict the responsiveness to neoadjuvant therapy, and has certain clinical value.

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Possibility of tuning the differentiation state of tumor associated macrophages towards tumor controlling phenotypes

10.7287/peerj.preprints.27747 ◽

2019 ◽

Author(s):

Wenfa Ng

Keyword(s):

Gene Expression ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Immune Cells ◽

Cellular Differentiation ◽

Expression Patterns ◽

Gene Cassette ◽

Gene Expression Patterns ◽

M2 Macrophages ◽

M1 And M2 Macrophages

Although various immune cells could infiltrate the cellular and tissue environment surrounding a tumor, the tumor microenvironment nevertheless presents immunosuppressive conditions unfavorable for immune cells to conduct large scale attack on cancer cells. For example, T-cells that make it to the tumor microenvironment are typically non-functional in containing tumor growth. On the other hand, macrophages could infiltrate the tumor microenvironment and is an important cell type modulated by and which also modulates the tumor. Specifically, two variants of macrophages with different phenotypes are known to exhibit close interactions with tumors. Known as M1 and M2 macrophages, they present dichotomously different signals to the tumor. Specifically, M1 macrophages control tumor growth while M2 macrophages promote tumor growth. Thus, from a treatment perspective, it would be desirable to tune the phenotypes and cell differentiation program of macrophages towards the M1 subset. To do that, differential gene expression of macrophages in the M1 and M2 lineages must be understood. Such a goal could be achieved with the profiling of tumor associated macrophages from tumor biopsy samples for gene expression patterns characteristic of the two dominant macrophage lineages. Single cell RNA-sequencing conducted after flow cytometry sorting of M1 and M2 macrophages would highlight gene expression patterns associated with each lineage, and the cellular differentiation programs that prompted entry into particular macrophage subtype. Knowledge of gene expression pattern associated with each macrophage lineage is not useful for tuning their differentiation state unless specific transcription factor that trigger the regulon could be identified. To this end, transcription factors that have been upregulated in the differentiation program could be profiled from the transcriptome data, and help inform the design of vectors for targeted overexpression of specific transcription factor for modulating cellular differentiation of macrophage. Given their low immunogenicity, adeno-associated virus (AAV) could serve as vectors for ferrying the gene cassette containing specific transcription factors into macrophages. Delivery methods for the AAV could be via targeted local infusion of vectors to tumors or through the systemic circulation, but the latter approach would result in lower transfection efficiency. Collectively, possibility exists of tuning the differentiation state of macrophage associated with tumors for enabling tumor controlling lineage to be dominant. Such immuno-targeted therapy would harness the body’s macrophages for controlling tumor growth and represents a treatment option that may yield fewer side effects compared to conventional chemotherapy. But, identification of genes that control lineage-specific differentiation program and the delivery of gene cassette to macrophages for modulating their differentiation remain key challenges.

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TAMI-32. CORRELATION BETWEEN RADIOSENSITIVITY INDEX AND M2 MACROPHAGE PROPORTION IN TUMOR MICROENVIRONMENT OF GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.816 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi204-vi205

Author(s):

Bum-Sup Jang ◽

In Ah Kim

Keyword(s):

Overall Survival ◽

Tumor Microenvironment ◽

Single Cell ◽

Rna Sequencing ◽

The Cancer Genome Atlas ◽

M2 Macrophage ◽

M2 Macrophages ◽

M1 Macrophage ◽

Single Cell Rna Sequencing ◽

Genome Atlas

Abstract BACKGROUND Tumor-associated macrophages (TAMs) Macrophage are predominant in glioblastoma tumor microenvironment (TME), supporting for neoplastic cell expansion and invasion. We investigated the relationship between radiosensitivity of glioblastoma and M1/M2 macrophage profiles in bulk and single cell RNA sequencing datasets. METHODS We used radiosensitivity index (RSI) gene signature and estimated RSI score based on the ranking of genes by expression level. Two large glioma datasets – The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) – were employed to identify whether RSI is clinically predictive of overall survival following radiation therapy. To analyze the association between M1/M2 macrophages and RSI within spatial context, the Ivy Glioblastoma Atlas Project dataset was investigated and single cell RNA sequencing dataset (GSE84465) was analyzed as well. Macrophages were profiled using a deconvolution algorithm, CIBERSORTx. RESULTS The RSI-high group having radioresistant tumors showed worse overall survival than the RSI-low group in both the TCGA (HR=1.87, 95% CI=1.06-3.29, P=0.031) and the CGGA (HR=1.61, 95% CI=1.04-2.50, P=0.031) glioblastoma population. In the Ivy Glioblastoma Atlas Project dataset, radiosensitive tumor having lower RSI was significantly more found in more vascular region including hyperplastic and microvascular region (coefficient=-0.07, P=0.001), meanwhile, radioresistant tumor was significantly clustered in necrotic region including perinecrotic and pseudopalisading regions (coefficient=0.07, P< 0.001). The proportion of M1/M2 macrophage and RSI score showed an inverse relationship (coefficient=-0.23, P=0.015), indicating that radioresistant glioblastomas are related with TME having more M2 than M1 macrophage. In single cell RNA sequencing dataset composed of immune and tumor cells collected from four patients, mean RSI of neoplastic cells was positively correlated with high proportion of M2 macrophages. CONCLUSION RSI can predict radiation response in terms of overall survival in glioblastoma patients. High proportion of M2 macrophage may play an important role in TME of radioresistant glioblastoma.

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LncRNA HOTAIR in Tumor Microenvironment: What Role?

International Journal of Molecular Sciences ◽

10.3390/ijms20092279 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2279 ◽

Cited By ~ 15

Author(s):

Gerardo Botti ◽

Giosuè Scognamiglio ◽

Gabriella Aquino ◽

Giuseppina Liguori ◽

Monica Cantile

Keyword(s):

Gene Expression ◽

Tumor Microenvironment ◽

Intracellular Signaling ◽

Regulation Of Gene Expression ◽

Tumor Evolution ◽

Metastatic Progression ◽

Cellular Processes ◽

Cellular Components ◽

Lncrna Hotair

lncRNAs participate in many cellular processes, including regulation of gene expression at the transcriptional and post-transcriptional levels. In addition, many lncRNAs can contribute to the development of different human diseases including cancer. The tumor microenvironment (TME) plays an important role during tumor growth and metastatic progression, and most of these lncRNAs have a key function in TME intracellular signaling. Among the numerous identified lncRNAs, several experimental evidences have shown the fundamental role of the lncRNA HOTAIR in carcinogenesis, also highlighting its use as a circulating biomarker. In this review we described the contribution of HOTAIR in the TME modulation, highlighting its relation with cellular and non-cellular components during tumor evolution and progression.

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High Expression of NREP Correlated With Worse Survival and M2 Macrophage Infiltrates in Gastric Cancer

10.21203/rs.3.rs-832381/v1 ◽

2021 ◽

Author(s):

Tailiang Lu ◽

Chenlong Li ◽

Wei Peng ◽

Cailing Xiang ◽

Yongqiang Gong ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

T Cell ◽

Mrna Expression ◽

Inflammatory Responses ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

High Expression ◽

M2 Macrophage ◽

M2 Macrophages

Abstract Background: Neuronal Regeneration Related Protein (NREP) is a highly conserved protein and is a newly discovered protein that may be closely related to tumor cell migration. We aim at investigating the prognostic role of NREP in gastric cancer (GC). Methods: Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analysis NREP mRNA expression in GC. Correlations between NREP mRNA expression and clinicopathological characteristic were analyzed. TCGA and GEO data were analyzed by The Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter databases respectively to assess prognostic value of NREP in GC. Gene set enrichment analysis (GSEA) was performed to identify the keg pathways related to NREP expression. TIMER and CIBERSORT analysis were used to found tumor-infiltrating immune cells associated with NREP mRNA expression. Results: NREP was over expressed in GC and significantly associated with T stage (P<0.001), Histologic grade (P = 0.022) and OS events (P = 0.007) of GC patients. High mRNA expression of NREP correlated with worse survival. The significantly kegg pathways enriched in samples with NREP high expression involved in cell adhesion, tumorigenesis, and immune and inflammatory responses. NREP mRNA expression was positively associated with CD4+T cell(r = 0.294, P = 1.04e−08), CD8+T cell(r = 0.125, P = 0.0167), Neutrophil(r = 0.169, P = 0.00116), Dendritic(r = 0.314, P = 1.03e−09), and was strongly associated with Macrophage (r = 0.547, P = 5.44e−30). The CIBERSORT database revealed that NREP mRNA expression was correlated with the activated memory CD4+ T cells(p<0.01), Monocytes(p<0.001) and M2 Macrophages(p<0.001). NREP is strongly correlated with the markers genes of M2 macrophages and tumor-associated macrophages (TAMs). Conclusion: NREP might be served as a novel prognostic biomarker of GC and associated with M2 macrophage infiltrates.

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