Immune Infiltration, Cancer Stemness, and Targeted Therapy in Gastrointestinal Stromal Tumor

ObjectiveTo investigate the characteristics of the tumor immune microenvironment in patients with gastrointestinal stromal tumor (GIST) and identify cancer stem-like properties of GIST to screen potential druggable molecular targets.MethodsThe gene expression data of 60 patients with GIST was retrieved from the Array Express database. CIBERSORT was applied to calculate the level of immune infiltration. ssGSEA and ESTIMATE were used to calculate the cancer stemness index and tissue purity. The Connectivity Map (CMAP) database was implemented to screen targeted drugs based on cancer stem-like properties of GIST.ResultThere was a difference in the level of immune infiltration between the metastasis and non-metastasis GIST groups. The low level of T-cell infiltration was correlated with high tumor purity and tumor stemness index, and the correlation coefficients were -0.87 and -0.61 (p < 0.001), respectively. Furthermore, there was a positive correlation between cancer stemness index and cell purity (p < 0.001). The cancer stemness index in the metastasis group was higher than that in the non-metastasis group (p = 0.0017). After adjusting for tumor purity, there was no significant correlation between T-cell infiltration and cancer stemness index (p = 0.086). Through the pharmacological mechanism of topoisomerase inhibitors, six molecular complexes may be the targets of GIST treatment.ConclusionImmune infiltration in GIST patients is related to cancer stem-like properties, and the correlation relies on tumor purity. Cancer stemness index can be used as a new predictive biomarker of tumor metastasis and targets of drug therapy for GIST patients.

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The landscape of T cell infiltration in human cancer and its association with antigen presenting gene expression

10.1101/025908 ◽

2015 ◽

Cited By ~ 13

Author(s):

Yasin Senbabaoglu ◽

Andrew G Winer ◽

Ron S Gejman ◽

Ming Liu ◽

Augustin Luna ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Immune Cell ◽

T Cell Subsets ◽

Cell Infiltration ◽

Th2 Cells ◽

Immune Infiltration ◽

T Cell Infiltration ◽

Mutation Burden ◽

Antigen Presenting

Infiltrating T cells in the tumor microenvironment have crucial roles in the competing processes of pro-tumor and anti-tumor immune response. However, the infiltration level of distinct T cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery (APM) genes, remain poorly characterized across human cancers. Here, we define a novel mRNA-based T cell infiltration score (TIS) and profile infiltration levels in 19 tumor types. We find that clear cell renal cell carcinoma (ccRCC) is the highest for TIS and among the highest for the correlation between TIS and APM expression, despite a modest mutation burden. This finding is contrary to the expectation that immune infiltration and mutation burden are linked. To further characterize the immune infiltration in ccRCC, we use RNA-seq data to computationally infer the infiltration levels of 24 immune cell types in a discovery cohort of 415 ccRCC patients and validate our findings in an independent cohort of 101 ccRCC patients. We find three clusters of tumors that are primarily separated by levels of T cell infiltration and APM gene expression. In ccRCC, the levels of Th17 cells and the ratio of CD8+ T/Treg levels are associated with improved survival whereas the levels of Th2 cells and Tregs are associated with negative clinical outcome. Our analysis illustrates the utility of computational immune cell decomposition for solid tumors, and the potential of this method to guide clinical decision-making.

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Identification SPTA1 Mutation as a Positive Predictive Biomarker for Immunotherapy by Associating with Cd8 + T Cell Infiltration in Lung Adenocarcinoma

SSRN Electronic Journal ◽

10.2139/ssrn.3878833 ◽

2021 ◽

Author(s):

Teng Li ◽

Han Wang ◽

Yang Lin ◽

Weihua Li ◽

Lin Dong ◽

...

Keyword(s):

T Cell ◽

Lung Adenocarcinoma ◽

Predictive Biomarker ◽

Cell Infiltration ◽

T Cell Infiltration

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Overexpression of LILRB2 (ILT4) is correlated with immunosuppressive immune infiltration in lung adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20519 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20519-e20519

Author(s):

Butuo Li ◽

Chao Jiang ◽

Shijiang Wang ◽

Xuanzong Li ◽

Yiyue Xu ◽

...

Keyword(s):

T Cell ◽

Lung Adenocarcinoma ◽

Objective Response ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Cell Infiltration ◽

M2 Macrophage ◽

Immune Infiltration ◽

T Cell Infiltration ◽

The Relationship

e20519 Background: Immune checkpoint inhibitors have revolutionized the patterns of tumor treatment with significantly improved survival. However, it’s worth noting that the objective response rate of PD-1/PD-L1 inhibitors monotherapy is just 20% in non-small cell lung cancer (NSCLC) patients, and biomarkers for the prognosis of patients receiving PD-1/PD-L1 inhibitors are urgently needed. LILRB2 (ILT4) is known as an immunosuppressive molecule and promotes the development and progression of NSCLC. However, the relationship between LILRB2 expression and immune microenvironment remains unclear in patients with lung adenocarcinoma. Methods: Expression profile and corresponding clinicopathological data of patients with lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) database. TIMER 2.0 was used to investigate the relationship between LILRB2 expression and immune infiltrates, including T cell subset, macrophage and so on. Cox proportional hazard model was also performed to evaluate the role LILRB2 expression and immune infiltrations in prognostic prediction of patients with lung adenocarcinoma. Results: 515 patients with lung adenocarcinoma were included in analysis from TCGA dataset. LILRB2 expression was found to have significant negative correlation with CD8+ T cell infiltration (P = 0.0012), and positive correlation with CD4+ T cell infiltration (P < 0.001). There were also significant positive correlations between LILRB2 expression and Treg (P = 0.0083), cancer associated fibroblast (P < 0.001), monocyte (P < 0.001), M2 macrophage (P < 0.001) infiltration, which was regarded as the marker of immunosuppressive microenvironment. Notably, there were also significant association between the expression of LILRB2 and PD-1 (P < 0.001) and PD-L1(P < 0.001). In terms of survival analysis, high level of Treg (HR = 0.86, P = 0.03) and M2 macrophage (HR = 0.84, P = 0.017) infiltration was associated with poor prognosis of patients with lung adenocarcinoma. However, the level of CD8+T cell (HR = 0.93, P = 0.298), CD4+ T cell (HR = 0.933, P = 0.321), and LILRB2 expression (P = 0.56) was not associated with the survival of patient with lung adenocarcinoma. Conclusions: The overexpression of LILRB2 is significantly correlated with immunosuppressive immune infiltration and microenvironment in lung adenocarcinoma and might be the potential predictive biomarkers for the PD-1/PD-L1 inhibitors.

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High IRF8 expression correlates with CD8 T cell infiltration and is a predictive biomarker of therapy response in ER-negative breast cancer

Breast Cancer Research ◽

10.1186/s13058-021-01418-7 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Gerardo Gatti ◽

Courtney Betts ◽

Darío Rocha ◽

Maribel Nicola ◽

Verónica Grupe ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Therapeutic Response ◽

Therapy Response ◽

Predictive Biomarker ◽

Cell Infiltration ◽

Neoplastic Cells ◽

T Cell Infiltration ◽

Immune Contexture ◽

The Relationship

Abstract Background Characterization of breast cancer (BC) through the determination of conventional markers such as ER, PR, HER2, and Ki67 has been useful as a predictive and therapeutic tool. Also, assessment of tumor-infiltrating lymphocytes has been proposed as an important prognostic aspect to be considered in certain BC subtypes. However, there is still a need to identify additional biomarkers that could add precision in distinguishing therapeutic response of individual patients. To this end, we focused in the expression of interferon regulatory factor 8 (IRF8) in BC cells. IRF8 is a transcription factor which plays a well-determined role in myeloid cells and that seems to have multiple antitumoral roles: it has tumor suppressor functions; it acts downstream IFN/STAT1, required for the success of some therapeutic regimes, and its expression in neoplastic cells seems to depend on a cross talk between the immune contexture and the tumor cells. The goal of the present study was to examine the relationship between IRF8 with the therapeutic response and the immune contexture in BC, since its clinical significance in this type of cancer has not been thoroughly addressed. Methods We identified the relationship between IRF8 expression and the clinical outcome of BC patients and validated IRF8 as predictive biomarker by using public databases and then performed in silico analysis. To correlate the expression of IRF8 with the immune infiltrate in BC samples, we performed quantitative multiplex immunohistochemistry. Results IRF8 expression can precisely predict the complete pathological response to monoclonal antibody therapy or to select combinations of chemotherapy such as FAC (fluorouracil, adriamycin, and cytoxan) in ER-negative BC subtypes. Analysis of immune cell infiltration indicates there is a strong correlation between activated and effector CD8+ T cell infiltration and tumoral IRF8 expression. Conclusions We propose IRF8 expression as a potent biomarker not only for prognosis, but also for predicting therapy response in ER-negative BC phenotypes. Its expression in neoplastic cells also correlates with CD8+ T cell activation and infiltration. Therefore, our results justify new efforts towards understanding mechanisms regulating IRF8 expression and how they can be therapeutically manipulated.

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