scholarly journals NRF2 Participates in the Suppressive Tumor Immune Microenvironment of KRAS/KEAP1 Co-Mutant Non-Small Cell Lung Cancer by Inhibiting the STING Pathway

2022 ◽  
Author(s):  
Xiaodan Sun ◽  
Peiyan Zhao ◽  
Hui Li ◽  
Yan liu ◽  
Ying Cheng
Keyword(s):  
Checkpoint Inhibitors ◽  
Poor Response ◽  
Subcellular Location ◽  
Negative Regulator ◽  
Luciferase Reporter ◽  
Immune Microenvironment ◽  
Promising Therapeutic Approach ◽  
Tumor Immune Microenvironment ◽  
Mrna And Protein Expression ◽  
Sting Pathway

Abstract Background: KRAS/KEAP1 (KK) co-mutant lung adenocarcinoma (LUAD) exhibited poor response to immune checkpoint inhibitors (ICI) via shaping a suppressive tumor immune microenvironment, the mechanism remains to be elucidated. Methods: The mRNA and protein expression of target molecules were analyzed by qRT-PCR and Western blot, respectively. The subcellular location of NRF2 was observed by immunofluorescence staining, and nuclear and cytoplasm isolation. After exogenous over-expression and knockdown of NRF2 and the addition of a STING pathway inhibitor in tumor cells, the effects on the CD8+ T cell recruitment was detected using chemotaxis assay, and the secretion of chemokines CCL5 and CXCL10 was analyzed by ELISA. The potential NRF2 target BRCA1 was identified using bioinformatic approaches and verified by a dual luciferase reporter assay. Results: NRF2, the target of KEAP1, was overexpressed and activated in KK type cells. NRF2 effected as a negative regulator of CD8+ T cells recruitment by decreasing CCL5 and CXCL10 chemokines in KK type LUAD. Mechanistically, NRF2 promoted the transcription and expression of BRCA1 to repair DNA damage, resulting in STING pathway inactivation. Conclusion: The combination of NRF2 inhibitor or STING agonist with ICI may be a promising therapeutic approach for patients with KK type LUAD.

scholarly journals Potential for treatment benefit of STING agonists plus immune checkpoint inhibitors in oral squamous cell carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chao Zhu ◽  
Jiang Li ◽  
Mianfeng Yao ◽  
Changyun Fang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Biological Pathways ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Sting Pathway ◽  
Immune Related Genes

Abstract Background DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) and its downstream signaling effector stimulator of interferon genes (STING) present a novel role in anti-tumor immunity. Recently, the combination of cGAS-STING agonists and immunotherapy achieved promising results in some tumor types. The correlation between cGAS-STING signaling pathway and the tumor immune microenvironment in patients with oral squamous cell carcinoma (OSCC) is unclear. Methods We utilized RNA sequencing and clinical data of OSCC patients from the TCGA database to investigate the correlation between cGAS-STING signaling pathway and the tumor immune microenvironment. Six cGAS-STING related genes were obtained from previous studies to establish the enrichment score of cGAS-STING pathway. The differences in survival rate, immune cell infiltration, immune-related genes expression and immune-related biological pathways were studied in the cGAS-STING clusters. Results We observed a better prognosis of OSCC patients in the cGAS-STING high cluster. The infiltration ratio of immune cells and the expression profiles of immune-related genes were elevated when the cGAS-STING pathway is activated. The differentially expressed genes between high and low cGAS-STING clusters were enriched in immune-related biological pathways. Conclusions Our findings suggest the potential benefit of combining STING agonists and immune checkpoint inhibitors in OSCC patients.

scholarly journals 250 Spatial-transcriptomic analysis of tumor-immune microenvironment in AML patients receiving pembrolizumab and decitabine

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A270-A270
Author(s):  
Chen Zhao ◽  
Abigail Wong-Rolle ◽  
Prajan Divakar ◽  
Katherine Calvo ◽  
Christopher Hourigan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Transcriptomic Analysis ◽  
Inadequate Response ◽  
Immune Microenvironment ◽  
Clinical Center ◽  
Tumor Immune Microenvironment ◽  
Refractory Acute Myeloid Leukemia

BackgroundRelapsed or refractory Acute Myeloid Leukemia (R-AML) is a deadly disease with an inadequate response rate to current treatments. Recent advances in immunotherapy shed light on R-AML, and several clinical trials have shown promising potential for combining immune checkpoint inhibitors (ICIs) with hypomethylating agents. A deeper understanding of the tumor-immune microenvironment in R-AML during combination ICI treatment is urgently needed for developing better therapeutics and stratifying treatment strategies.MethodsTo dissect the tumor-immune interactions in the bone marrow microenvironment, we employed nanoString GeoMx Digital Spatial Profiler (DSP) and performed a spatial-transcriptomic analysis of patients with R-AML who received pembrolizumab and decitabine. We compared the transcriptomic profiles and TCR clonalities of tumor-interacting T cells, bystander T cells, and other cells at baseline, post-pembrolizumab treatment, and post-decitabine, which enable us to identify R-AML’s suppressive immune microenvironment and immune cells’ responses to ICI and hypomethylating agent.ResultsWe obtained the spatial-transcriptomic profiles of T cells, stromal cells, and leukemia cells in patients with R-AML at different treatment points. Our TCR-specific probes were able to track T cell clonal changes during treatments.ConclusionsR-AML harbored a complex tumor immune microenvironment and diverse T cell clonality.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NHLBI, and NIH Clinical Center.Ethics ApprovalThis study is approved by NHLBI IRB.

scholarly journals Characterization of the m6A-Associated Tumor Immune Microenvironment in Prostate Cancer to Aid Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Zezhen Liu ◽  
Jiehui Zhong ◽  
Jie Zeng ◽  
Xiaolu Duan ◽  
Jianming Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Poor Prognosis ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
Intratumor Heterogeneity ◽  
Immune Microenvironment ◽  
Th2 Cell ◽  
Tumor Immune Microenvironment

The aim of this study was to elucidate the correlation between m6A modification and the tumor immune microenvironment (TIME) in prostate cancer (PCa) and to identify the m6A regulation patterns suitable for immune checkpoint inhibitors (ICIs) therapy. We evaluated the m6A regulation patterns of PCa based on 24 m6A regulators and correlated these modification patterns with TIME characteristics. Three distinct m6A regulation patterns were determined in PCa. The m6A regulators cluster with the best prognosis had significantly increased METTL14 and ZC3H13 expression and was characterized by low mutation rate, tumor heterogeneity, and neoantigens. The m6A regulators cluster with a poor prognosis had markedly high KIAA1429 and HNRNPA2B1 expression and was characterized by high intratumor heterogeneity and Th2 cell infiltration, while low Th17 cell infiltration and Macrophages M1/M2. The m6Ascore was constructed to quantify the m6A modification pattern of individual PCa patients based on m6A-associated genes. We found that the low-m6Ascore group with poor prognosis had a higher immunotherapeutic response rate than the high-m6Ascore group. The low-m6Ascore group was more likely to benefit from ICIs therapy. This study was determined that immunotherapy is more effective in low-m6Ascore PCa patients with poor prognosis.

scholarly journals Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 79 ◽  
Author(s):  
Julijan Kabiljo ◽  
Felix Harpain ◽  
Sebastian Carotta ◽  
Michael Bergmann
Keyword(s):  
Cell Death ◽  
Clinical Studies ◽  
Checkpoint Inhibitors ◽  
External Beam Radiotherapy ◽  
Local Treatment ◽  
Immunogenic Cell Death ◽  
Immune Microenvironment ◽  
Anti Cancer ◽  
Tumor Immune Microenvironment ◽  
Radiation Induced

Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies combining radiotherapy with immunotherapies suggest a synergistic potential of this approach. Improving our understanding of how radiation reconditions the tumor immune microenvironment should pave the way for designing rational and robust combinations with immunotherapeutic drugs that enhance both local and systemic anti-cancer immune effects. In this review, we summarize irradiation-induced types of immunogenic cell death and their effects on the tumor microenvironment. We discuss preclinical insights on mechanisms and benefits of combining radiotherapy with immunotherapy, focusing on immune checkpoint inhibitors. In addition, we elaborate how these observations were translated into clinical studies and which parameters may be optimized to achieve best results in future clinical trials.

scholarly journals Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

2020 ◽  
Vol 111 (9) ◽  
pp. 3132-3141
Author(s):  
Yoshifumi Baba ◽  
Daichi Nomoto ◽  
Kazuo Okadome ◽  
Takatsugu Ishimoto ◽  
Masaaki Iwatsuki ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

scholarly journals Interactions Between Anti-Vegf Therapy and Antitumor Immunity as a Potential Therapeutic Strategy in Colorectal Cancer

2019 ◽  
Vol 62 (3) ◽  
pp. 127-130
Author(s):  
David Buka ◽  
Josef Dvořák ◽  
Igor Richter ◽  
Pavel Škrobánek ◽  
Tomáš Buchler ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Therapeutic Interventions ◽  
Successful Implementation ◽  
Immune Microenvironment ◽  
Combination Strategy ◽  
Vessel Normalization ◽  
Anti Vegf ◽  
Tumor Immune Microenvironment ◽  
General Response

There is a growing corpus of evidence indicating that anti-VEGF therapy may normalize the abnormal tumor vasculature with the potential to re-program the tumor immune microenvironment to a more immunosupportive profile. Tumor vessel normalization increases tumor perfusion, and, consequently, oxygen and nutrient supply, and thus can be assumed to improve the general response to anticancer immunotherapy. The increased antitumor immunity responses seen following anti-VEGF therapy may also be associated with the inhibition of the immunosuppressive action deployed by VEGF on effector T cells. Bearing in mind the recent advances of combination immunotherapy, combinations of anti-VEGF therapy with immune checkpoint inhibitors now appear to represent an attractive strategy. Key to the successful implementation of a combination strategy for treating cancer is understanding the interaction of these two therapeutic interventions, particularly in regards to appropriate reprogramming of the tumor immune microenvironment to improve antitumor immunity.

scholarly journals Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer

2020 ◽  
Vol 6 (20) ◽  
pp. eaba1590 ◽  
Author(s):  
Xue Dong ◽  
Pei Pan ◽  
Di-Wei Zheng ◽  
Peng Bao ◽  
Xuan Zeng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
In Vivo Studies ◽  
Host Immune System ◽  
Immune Microenvironment ◽  
Phage Display Technology ◽  
Tumor Immune Microenvironment

Mounting evidence suggests that the gut microbiota contribute to colorectal cancer (CRC) tumorigenesis, in which the symbiotic Fusobacterium nucleatum (Fn) selectively increases immunosuppressive myeloid-derived suppressor cells (MDSCs) to hamper the host’s anticancer immune response. Here, a specifically Fn-binding M13 phage was screened by phage display technology. Then, silver nanoparticles (AgNP) were assembled electrostatically on its surface capsid protein (M13@Ag) to achieve specific clearance of Fn and remodel the tumor-immune microenvironment. Both in vitro and in vivo studies showed that of M13@Ag treatment could scavenge Fn in gut and lead to reduction in MDSC amplification in the tumor site. In addition, antigen-presenting cells (APCs) were activated by M13 phages to further awaken the host immune system for CRC suppression. M13@Ag combined with immune checkpoint inhibitors (α-PD1) or chemotherapeutics (FOLFIRI) significantly prolonged overall mouse survival in the orthotopic CRC model.

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