scholarly journals LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer

2019 ◽  
Vol 20 (8) ◽  
pp. 1874 ◽  
Author(s):  
Laura Bonanno ◽  
Elisabetta Zulato ◽  
Alberto Pavan ◽  
Ilaria Attili ◽  
Giulia Pasello ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Redox Homeostasis ◽  
Suppressor Gene ◽  
Response To Treatment ◽  
Primary Resistance ◽  
Potential Applications ◽  
Liver Kinase B1 ◽  
Immunosuppressive Microenvironment ◽  
Tumor Types

Liver kinase B1 (LKB1) is a tumor suppressor gene whose inactivation is frequent in different tumor types, especially in lung adenocarcinoma (about 30% of cases). LKB1 has an essential role in the control of cellular redox homeostasis by regulating ROS production and detoxification. Loss of LKB1 makes the tumor cell more sensitive to oxidative stress and consequently to stress-inducing treatments, such as chemotherapy and radiotherapy. LKB1 loss triggers complex changes in tumor microenvironment, supporting a role in the regulation of angiogenesis and suggesting a potential role in the response to anti-angiogenic treatment. On the other hand, LKB1 deficiency can promote an immunosuppressive microenvironment and may be involved in primary resistance to anti-PD-1/anti-PD-L1, as it has been reported in lung cancer. The aim of this review is to discuss interactions of LKB1 with the tumor microenvironment and the potential applications of this knowledge in predicting response to treatment in lung cancer.

scholarly journals LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Francesco Ciccarese ◽  
Elisabetta Zulato ◽  
Stefano Indraccolo
Keyword(s):  
Cellular Response ◽  
Cell Metabolism ◽  
Redox Homeostasis ◽  
Suppressor Gene ◽  
Ampk Signaling ◽  
Promising Therapeutic Target ◽  
Liver Kinase B1 ◽  
Nsclc Patients ◽  
Tumor Types

Inactivating mutations of the tumor suppressor gene Liver Kinase B1 (LKB1) are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.

Targeting CD38 to improve anti-PD-1/CTLA-4 combination therapy in lung cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 144-144 ◽  
Author(s):  
Limo Chen ◽  
Yanli Li ◽  
Xiaohui Yi ◽  
Don Lynn Gibbons
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Primary Resistance ◽  
Lung Cancer Patients ◽  
Cd38 Expression ◽  
Pathologic Analysis ◽  
Cellular Immune

144 Background: The combination of anti-PD-1 and anti-CTLA-4 is a promising strategy that is being clinically explored to treat a variety of cancer types. Some patients display primary resistance to this combination treatment, while others relapse after treatment. Although some cancer patients have long-term durable responses to the combination therapy of anti-PD-1 and anti-CTLA-4, physicians have been looking for biomarkers that predict response. Methods: Using multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the mechanisms of resistance to anti-PD-1/CTLA-4 combination therapy by evaluating the molecular and cellular immune profiles of the tumor microenvironment. Antibody-mediated cell depletion assays were also conducted to validate the mechanisms. Lastly, to determine the applicability to patients, we analyzed 791 lung cancer patients’ specimens with immunohistochemistry staining and mined many immune markers in multiple large independent patient databases (~1900 tumors). Results: We observed that tumor bearing mice treated with combined PD-1 and CTLA-4 blocking antibodies developed resistance through the up-regulation of CD38, and that targeting CD38 abolished the resistance in a manner dependent on B7-costimulation. Additionally, combined PD-1 and CTLA-4 blockade eradicates CD38-deficient tumors in mice. Further study revealed that control of tumors by triple blockade of CD38, PD-1, and CTLA-4 depended on improved functionality of CD4+/CD8+ TILs, which were reactivated by enriched CD103+ dendritic cells in the tumor microenvironment. Pathologic analysis revealed positive immunohistochemical staining for CD38 on tumor cells in 15-23% of cases and bioinformatic analyses revealed a strong correlation between CD38 expression and an immune inflammatory signature. Conclusions: Targeting CD38 improves the efficacy of anti-PD-1/CTLA-4 combination therapy in lung cancer. CD38 on tumor cells could potentially serve as a novel biomarker of resistance for immune checkpoint inhibition.

scholarly journals PET/CT Radiomics in Lung Cancer: An Overview

2020 ◽  
Vol 10 (5) ◽  
pp. 1718 ◽  
Author(s):  
Francesco Bianconi ◽  
Isabella Palumbo ◽  
Angela Spanu ◽  
Susanna Nuvoli ◽  
Mario Luca Fravolini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Large Scale ◽  
Field Analysis ◽  
Response To Treatment ◽  
Computer Assisted ◽  
Imaging Features ◽  
Research Attention ◽  
Full Field ◽  
Pet Ct ◽  
Potential Applications

Quantitative extraction of imaging features from medical scans (‘radiomics’) has attracted a lot of research attention in the last few years. The literature has consistently emphasized the potential use of radiomics for computer-assisted diagnosis, as well as for predicting survival and response to treatment. Radiomics is appealing in that it enables full-field analysis of the lesion, provides nearly real-time results, and is non-invasive. Still, a lot of studies suffer from a series of drawbacks such as lack of standardization and repeatability. Such limitations, along with the unmet demand for large enough image datasets for training the algorithms, are major hurdles that still limit the application of radiomics on a large scale. In this paper, we review the current developments, potential applications, limitations, and perspectives of PET/CT radiomics with specific focus on the management of patients with lung cancer.

scholarly journals Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 986
Author(s):  
Nada S. Aboelella ◽  
Caitlin Brandle ◽  
Timothy Kim ◽  
Zhi-Chun Ding ◽  
Gang Zhou
Keyword(s):  
Oxidative Stress ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Redox Homeostasis ◽  
Tumor Rejection ◽  
Oxygen Species ◽  
Antitumor Effects ◽  
Key Drivers ◽  
Cancer Immunotherapies ◽  
The Impact

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

scholarly journals Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Clément Meiller ◽  
François Montagne ◽  
Theo Z. Hirsch ◽  
Stefano Caruso ◽  
Julien de Wolf ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Malignant Pleural Mesothelioma ◽  
Tumor Heterogeneity ◽  
Immunological Synapse ◽  
Side Wall ◽  
Molecular Classification ◽  
Suppressor Gene ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Methylome Analysis

Abstract Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

scholarly journals Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Donghong Zhang ◽  
Jinfeng Ning ◽  
Imoh Okon ◽  
Xiaoxu Zheng ◽  
Ganesh Satyanarayana ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epigenetic Modification ◽  
Suppressor Gene ◽  
Ctcf Binding ◽  
Binding Motif ◽  
Loss Of Function ◽  
Dna Hypermethylation ◽  
Lung Cancer Patients ◽  
Lkb1 Tumor Suppressor ◽  
And Migration

AbstractOncogenic KRAS mutations combined with the loss of the LKB1 tumor-suppressor gene (KL) are strongly associated with aggressive forms of lung cancer. N6-methyladenosine (m6A) in mRNA is a crucial epigenetic modification that controls cancer self-renewal and progression. However, the regulation and role of m6A modification in this cancer are unclear. We found that decreased m6A levels correlated with the disease progression and poor survival for KL patients. The correlation was mediated by a special increase in ALKBH5 (AlkB family member 5) levels, an m6A demethylase. ALKBH5 gain- or loss-of function could effectively reverse LKB1 regulated cell proliferation, colony formation, and migration of KRAS-mutated lung cancer cells. Mechanistically, LKB1 loss upregulated ALKBH5 expression by DNA hypermethylation of the CTCF-binding motif on the ALKBH5 promoter, which inhibited CTCF binding but enhanced histone modifications, including H3K4me3, H3K9ac, and H3K27ac. This effect could successfully be rescued by LKB1 expression. ALKBH5 demethylation of m6A stabilized oncogenic drivers, such as SOX2, SMAD7, and MYC, through a pathway dependent on YTHDF2, an m6A reader protein. The above findings were confirmed in clinical KRAS-mutated lung cancer patients. We conclude that loss of LKB1 promotes ALKBH5 transcription by a DNA methylation mechanism, reduces m6A modification, and increases the stability of m6A target oncogenes, thus contributing to aggressive phenotypes of KRAS-mutated lung cancer.

scholarly journals Mast Cell-Derived SAMD14 is a Novel Regulator of the Human Prostate Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1237
Author(s):  
Linda K. H. Teng ◽  
Brooke A. Pereira ◽  
Shivakumar Keerthikumar ◽  
Cheng Huang ◽  
Birunthi Niranjan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Suppressor Gene ◽  
Prostate Tumor ◽  
Human Prostate ◽  
Proteomic Profiling ◽  
Putative Tumor Suppressor Gene ◽  
Invasion And Migration ◽  
And Migration

Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.

scholarly journals Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

2021 ◽  
Vol 9 (1) ◽  
pp. e001933
Author(s):  
Sophie M Poznanski ◽  
Tyrah M Ritchie ◽  
Isabella Y Fan ◽  
Abdullah El-Sayes ◽  
Ana L Portillo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Combined Treatment ◽  
Death Receptor ◽  
High Rate ◽  
Advanced Lung Cancer ◽  
Pd1 Blockade

Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1−blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients’ tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1− patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.

scholarly journals Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide

2021 ◽  
Author(s):  
M. Del Re ◽  
V. Conteduca ◽  
S. Crucitta ◽  
G. Gurioli ◽  
C. Casadei ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Clinical Outcome ◽  
Liquid Biopsy ◽  
Response To Treatment ◽  
First Line ◽  
Primary Resistance ◽  
Circulating Free Dna ◽  
Free Dna ◽  
Signaling Inhibitors

Abstract Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p < 0.0001). Median OS was significantly longer in AR normal vs patients with AR gain (not reached vs 8.17 months, p < 0.0001). A significant correlation between AR-V7 and AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001). Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

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