scholarly journals The Impact of Radiation on the Tumor Microenvironment: Effect of Dose and Fractionation Schedules

2018 ◽  
Vol 11 ◽  
pp. 117906441876163 ◽  
Author(s):  
Kimberly M Arnold ◽  
Nicole J Flynn ◽  
Adam Raben ◽  
Lindsay Romak ◽  
Yan Yu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
External Beam Radiotherapy ◽  
Tumor Stroma ◽  
Therapeutic Benefit ◽  
Normal Tissues ◽  
Technological Advances ◽  
Fractionation Schedule ◽  
Effects Of Radiation ◽  
Hypofractionated Radiation ◽  
The Impact

In addition to inducing lethal DNA damage in tumor and stromal cells, radiation can alter the interactions of tumor cells with their microenvironment. Recent technological advances in planning and delivery of external beam radiotherapy have allowed delivery of larger doses per fraction (hypofractionation) while minimizing dose to normal tissues with higher precision. The effects of radiation on the tumor microenvironment vary with dose and fractionation schedule. In this review, we summarize the effects of conventional and hypofractionated radiation regimens on the immune system and tumor stroma. We discuss how these interactions may provide therapeutic benefit in combination with targeted therapies. Understanding the differential effects of radiation dose and fractionation can have implications for choice of combination therapies.

scholarly journals CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1651
Author(s):  
María Auxiliadora Olivares-Urbano ◽  
Carmen Griñán-Lisón ◽  
Juan Antonio Marchal ◽  
María Isabel Núñez
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Epithelial Mesenchymal Transition ◽  
Treatment Modalities ◽  
Mesenchymal Transition ◽  
Normal Tissues ◽  
Combination Strategies ◽  
Technological Advances ◽  
Oncologic Treatment ◽  
The Impact

Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial–mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.

scholarly journals TAMI-11. IMPACT OF oHSV ACTIVATED NOTCH SIGNALING IN TUMOR MICROENVIRONMENT, AND ITS IMPACT ON ANTI-TUMOR IMMUNITY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii215-ii215
Author(s):  
Yoshihiro Otani ◽  
Ji Young Yoo ◽  
Samantha Chao ◽  
Toshihiko Shimizu ◽  
Cole Lewis ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Notch Signaling ◽  
Tumor Immunity ◽  
Cell Communication ◽  
Notch Signaling Pathway ◽  
Therapeutic Benefit ◽  
Notch Receptor ◽  
Negative Regulator ◽  
Gamma Secretase ◽  
The Impact

Abstract NOTCH signaling is a method of cell-cell communication where membrane bound NOTCH ligands on signal-sending cells can bind to and initiate cleavage of the NOTCH receptor, releasing NICD which can initiate signal transduction in adjacent “signal-receiving” cells. We have recently shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells. RNA sequencing of GBM cells post-infection also uncovered Gene Ontology NOTCH signaling pathway to be significantly upregulated. This activation was induced by viral miRNA-H16, which represses FIH-1 expression. FIH-1 was found to be a negative regulator of Mib1, a ubiquitin ligase, which activates NOTCH ligand-mediated activation of adjacent signal-receiving cells bearing the NOTCH receptor (Otani et al Clin. Can. Res. 2020). Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment. Treatment of brain tumors in immune competent mice with oHSV and NOTCH blocking gamma secretase inhibitor (GSI) induced an anti-tumor memory immune response. Long term survivors in mice treated with the combination also completely rejected subsequent tumor re-challenge in the other hemisphere. UMAP of flow cytometry of tumor-bearing hemispheres and functional analysis of isolated cellular fractions from treated mice showed a significant influx of MDSC cells after oHSV treatment that was rescued in mice treated with oHSV and GSI. Ongoing mechanistic studies are uncovering a significant induction of NOTCH in tumor associated macrophages that aids in recruitment of MDSC cells. Overall these studies have uncovered a significant impact of oHSV therapy on GBM tumor microenvironment and presents opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity.

scholarly journals IM-4 Impact of oHSV activated NOTCH signaling in tumor microenvironment and its impact on anti-tumor immunity

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi7-vi7
Author(s):  
Otani Yoshihiro ◽  
Ji Young Yoo ◽  
Sean E Lawler ◽  
Antonio E Chiocca ◽  
Balveen Kaur
Keyword(s):  
Tumor Microenvironment ◽  
Notch Signaling ◽  
Tumor Immunity ◽  
Myeloid Cell ◽  
Suppressor Cell ◽  
Therapeutic Benefit ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
The Impact ◽  
Recurrent Gbm

Abstract Oncolytic herpes simplex virus-1 (oHSV) is novel FDA-approved immunotherapy for advanced melanoma patients in US. Also, oHSV is recently approved for the treatment of recurrent GBM in Japan. We have shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells via HSV-1 microRNA-H16 (Otani Y and Yoo JY, Clin Cancer Res, 2020), however, the consequences of NOTCH on immunotherapy in GBM is unknow. Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment (TME). Analysis of TCGA GBM data and experimental murine models revealed NOTCH induced immunosuppressive myeloid cell recruitment and limited anti-tumor immunity. In oHSV treated tissue, viral infection educated tumor associated macrophages to secrete CCL2 which recruited monocytic myeloid derived suppressor cell (MDSC) that attenuated anti-tumor immunity. Consistent with this, CCL2 induction was also observed in serum of recurrent GBM patients treated with oHSV (NCT03152318). Importantly, blockade of NOTCH signaling reduced the oHSV induced immunosuppressive environment and activated a CD8 dependent anti-tumor memory response. These findings present the opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity in GBM.

scholarly journals Targeting the Tumor Microenvironment in Neuroblastoma: Recent Advances and Future Directions

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2057 ◽  
Author(s):  
Shweta Joshi
Keyword(s):  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Tumor Stroma ◽  
Genetic Alterations ◽  
Future Directions ◽  
Pediatric Tumor ◽  
Normal Tissues ◽  
Recent Advances ◽  
Future Potential

Neuroblastoma (NB) is the most common pediatric tumor malignancy that originates from the neural crest and accounts for more than 15% of all the childhood deaths from cancer. The neuroblastoma cancer research has long been focused on the role of MYCN oncogene amplification and the contribution of other genetic alterations in the progression of this malignancy. However, it is now widely accepted that, not only tumor cells, but the components of tumor microenvironment (TME), including extracellular matrix, stromal cells and immune cells, also contribute to tumor progression in neuroblastoma. The complexity of different components of tumor stroma and their resemblance with surrounding normal tissues pose huge challenges for therapies targeting tumor microenvironment in NB. Hence, the detailed understanding of the composition of the TME of NB is crucial to improve existing and future potential immunotherapeutic approaches against this childhood cancer. In this review article, I will discuss different components of the TME of NB and the recent advances in the strategies, which are used to target the tumor microenvironment in neuroblastoma.

scholarly journals The impact of the molecular profile of the tumor microenvironment on the prognosis of NSCLC

2021 ◽  
Author(s):  
Hangjie Ying ◽  
Qingqing Hang ◽  
Guoping Cheng ◽  
Shifeng Yang ◽  
Jianan Jin ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Tumor Microenvironment ◽  
Tumor Stroma ◽  
Tissue Microarrays ◽  
Clinicopathological Characteristics ◽  
Molecular Profile ◽  
Invasion And Metastasis ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
The Impact

Abstract Purpose The present study was performed to clarify the correlation between macrophages, tumor neo-vessels and programmed cell death-ligand 1 (PD-L1) in the tumor microenvironment (TME) and the clinicopathological features of non-small cell lung cancer (NSCLC) and to explore the prognostic factors of stromal features in NSCLC. Methods Tissue microarrays containing 92 NSCLC patients were studied with immunohistochemistry (IHC). The distribution and quantitative data of CD68- and CD206-positive tumor-associated macrophages (TAMs) in tumor islets and tumor stroma, and the expression of tumor neo‑vessels and PD-L1, were analyzed by inverted microscopy and Image-Pro Plus 6.0 software. Prognostic analyses with the clinicopathological characteristics and tumor microenvironment features were performed. Results The number of CD68-positive macrophages in each location of the tumor islets and tumor stroma was significantly higher than that of CD206-positive macrophages, and they were significantly correlated (P < 0.0001). Survival analysis revealed that CD68- and CD206-positive TAMs in the tumor stroma and tumor islets were significant prognostic factors (P < 0.05, respectively). Comprehensive analysis of CD206-positive stromal TAMs showed that CD105 and PD-L1 were significant prognostic factors (P=0.045). Moreover, CD68-positive TAMs in tumor islets and the expression of PD-L1 were independent predictors of poor prognosis for NSCLC. Conclusion Thus, the key elements in the tumor microenvironment, including tumor neo‑vessels, macrophages and PD-L1, were heterogenic in NSCLC tissues and had significant roles in cancer invasion and metastasis. The combined analysis of key components in the tumor microenvironment was an important prognostic factor.

scholarly journals Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity

2020 ◽  
Author(s):  
John P. Murad ◽  
Dileshni Tilakawardane ◽  
Anthony K. Park ◽  
Kelly T. Kennewick ◽  
Lupita S. Lopez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Therapy ◽  
Normal Tissues ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
The Impact

AbstractChimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed an in vivo requirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity.

Clinical evaluation of the effects of radiotherapy on oral mucosa and gingiva

2008 ◽  
Vol 7 (4) ◽  
pp. 195-204 ◽  
Author(s):  
M. Taheri ◽  
K. Sohrabi ◽  
M.H. Salehi ◽  
M.H. Najafi
Keyword(s):  
Head And Neck ◽  
Oral Mucosa ◽  
Radiation Dosage ◽  
Gingival Recession ◽  
Medical File ◽  
Normal Tissues ◽  
Periodontal Index ◽  
Assessment And Treatment ◽  
Effects Of Radiation ◽  
The Impact

AbstractIntroduction:The use of radiotherapy, alone or in conjunction with surgical resection, is common in treating head and neck tumours. However, ionising radiation induces unavoidable changes in the surrounding normal tissues, causing severe complications. Therefore, we decided to study different effects of radiotherapy on gingiva and oral mucosa.Methods and Materials:This prospective analytical study was performed on 30 patients with head and neck cancers referred to the radiotherapy department of Ghaem Hospital from March to October 2006. Data were collected by means of interviews, clinical examinations and patients’ medical file investigation. The impact of different dosages of radiation on gingiva and oral mucosa was investigated. Data analysis was performed using general linear model (GLM), Cochran and multivariate analysis of variance (MANOVA) tests via SPSS V. 11.5 software.Results:A direct relationship between increase in radiation dosage, irritation of oral mucosa, ulcer development and mucositis was observed. But there was no significant relationship between NUG (necrotising ulcerative gingivitis) and perlèche and radiation dosage. Periodontal index (PI), gingival index (GI) and papillary bleeding index (PBI) were increased, but due to limited time of study (6–7 weeks), no change in gingival recession was observed. Plaque index (PLI) decreased during treatment process because of oral hygiene instructions.Conclusion:The oral and periodontal health status of head and neck cancer patients before and during radiotherapy has been described in this article. The authors believe that prevention or reduction of side-effects of radiation should be an integral part of treatment as they may have tremendous effect on the patient's quality of life. This study supports the need for dental assessment and treatment planning before radiation therapy.

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 Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1850
Author(s):  
Justine Cinier ◽  
Margaux Hubert ◽  
Laurie Besson ◽  
Anthony Di Roio ◽  
Céline Rodriguez ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Poor Prognosis ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Major Function ◽  
Normal Tissues ◽  
Tumor Environment ◽  
Plastic Transformation

Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs’ deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.

scholarly journals 695 Oral delivery of a microbial extracellular vesicle induces potent anti-tumor immunity in mice

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A737-A737
Author(s):  
Loise Francisco-Anderson ◽  
Loise Francisco-Anderson ◽  
Mary Abdou ◽  
Michael Goldberg ◽  
Erin Troy ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Extracellular Vesicles ◽  
Tumor Immunity ◽  
Extracellular Vesicle ◽  
The Body ◽  
Checkpoint Inhibition ◽  
Small Intestinal ◽  
The Impact

BackgroundThe small intestinal axis (SINTAX) is a network of anatomic and functional connections between the small intestine and the rest of the body. It acts as an immunosurveillance system, integrating signals from the environment that affect physiological processes throughout the body. The impact of events in the gut in the control of tumor immunity is beginning to be appreciated. We have previously shown that an orally delivered single strain of commensal bacteria induces anti-tumor immunity preclinically via pattern recognition receptor-mediated activation of innate and adaptive immunity. Some bacteria produce extracellular vesicles (EVs) that share molecular content with the parent bacterium in a particle that is roughly 1/1000th the volume in a non-replicating form. We report here an orally-delivered and gut-restricted bacterial EV which potently attenuates tumor growth to a greater extent than whole bacteria or checkpoint inhibition.MethodsEDP1908 is a preparation of extracellular vesicles produced by a gram-stain negative strain of bacterium of the Oscillospiraceae family isolated from a human donor. EDP1908 was selected for its immunostimulatory profile in a screen of EVs from a range of distinct microbial strains. Its mechanism of action was determined by ex vivo analysis of the tumor microenvironment (TME) and by in vitro functional studies with murine and human cells.ResultsOral treatment of tumor-bearing mice with EDP1908 shows superior control of tumor growth compared to checkpoint inhibition (anti-PD-1) or an intact microbe. EDP1908 significantly increased the percentage of IFNγ and TNF producing CD8+ CTLs, NK cells, NKT cells and CD4+ cells in the tumor microenvironment (TME). EDP1908 also increased tumor-infiltrating dendritic cells (DC1 and DC2). Analysis of cytokines in the TME showed significant increases in IP-10 and IFNg production in mice treated with EDP1908, creating an environment conducive to the recruitment and activation of anti-tumor lymphocytes.ConclusionsThis is the first report of striking anti-tumor effects of an orally delivered microbial extracellular vesicle. These data point to oral EVs as a new class of immunotherapeutic drugs. They are particularly effective at harnessing the biology of the small intestinal axis, acting locally on host cells in the gut to control distal immune responses within the TME. EDP1908 is in preclinical development for the treatment of cancer.Ethics ApprovalPreclinical murine studies were conducted under the approval of the Avastus Preclinical Services’ Ethics Board. Human in vitro samples were attained by approval of the IntegReview Ethics Board; informed consent was obtained from all subjects.

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