scholarly journals ANGI-1 Impact of neoadjuvant bevacizumab on transcriptional factor for stemness, macrophage polarization, and oxygenation of tumor microenvironment in glioblastoma

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi1-vi1
Author(s):  
Toshihide Tanaka ◽  
Jun Takei ◽  
Akihiko Teshigawara ◽  
Kyoichi Tohmoto ◽  
Yohei Yamamoto ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Regression ◽  
Macrophage Polarization ◽  
Poor Responder ◽  
Tumor Oxygenation ◽  
Newly Diagnosed ◽  
Good Responder ◽  
Regression Rate ◽  
Paired Samples ◽  
Foxm1 Expression

Abstract Background: Previously we reported that bevacizumab (Bev) produces tumor oxygenation with immunosupportive tumor microenvironment (TME) and inhibition of stemness. To confirm whether those effects might contribute prolongation of clinical outcome, in the present study paired samples from same patients with newly diagnosed GBM who received Bev during its effectiveness and refractoriness were investigated by immunohistochemistry. Methods: Eighteen samples from 9 patients with newly diagnosed GBM who received preoperative neoadjuvant Bev (neoBev) followed by surgical operation and chemoradiotherapy in addition to salvage surgery after recurrence were investigated. Expressions of FOXM1, HIF-1, and CD163 were evaluated by immunohistochemistry. Overall survial (OS) were analyzed with the present cohort divided into two groups between good and poor responder (GR and PR, respectively) of Bev defined as tumor regression rate judged by T1 gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) images. Results: In the group of good responder of T1Gd (T1Gd-GR; defined as >38% of regression rate after neoBev), OS was prolonged compared with T1Gd-PR along with inhibition of FOXM1 expression and HIF-1a. In contrast, in the group of good responder of FLAIR (FLAIR-GR; defined as >54% of regression rate after neoBev), there were no significant differences of OS and FOXM1 expression between GR and PR. HIF-1a expression tended to be elevated in T1Gd-PR of initial tumors, T1Gd-GR of recurrent tumors, and FLAIR-PR of both initial and recurrent tumors.Conclusion: T1Gd-GR after neoBev might attribute to inhibition of FOXM1 and oxygenation. Bev might provide tumor oxygenation, leading to inhibition of stemness and M2 TAM infiltration during its effectiveness. These results suggested that Bev combined with immunotherapy for newly diagnosed GBM might provide clinical benefits including inhibition of stemness and induction of immunosupportive TME, when tumor volume assessed by T1 Gd. was significantly decreased following neoBev.

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 Field Cancerization in NSCLC: A New Perspective on MicroRNAs in Macrophage Polarization

2021 ◽  
Vol 22 (2) ◽  
pp. 746
Author(s):  
Radu Pirlog ◽  
Andrei Cismaru ◽  
Andreea Nutu ◽  
Ioana Berindan-Neagoe
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Respiratory Tract ◽  
Macrophage Polarization ◽  
Cell Communication ◽  
Premalignant Lesions ◽  
Field Cancerization ◽  
Dynamic Interactions ◽  
Lung Cancers ◽  
New Perspective

Lung cancer is currently the first cause of cancer-related death. The major lung cancer subtype is non-small cell lung cancers (NSCLC), which accounts for approximatively 85% of cases. The major carcinogenic associated with lung cancer is tobacco smoke, which produces long-lasting and progressive damage to the respiratory tract. The progressive and diffuse alterations that occur in the respiratory tract of patients with cancer and premalignant lesions have been described as field cancerization. At the level of tumor cells, adjacent tumor microenvironment (TME) and cancerized field are taking place dynamic interactions through direct cell-to-cell communication or through extracellular vesicles. These molecular messages exchanged between tumor and nontumor cells are represented by proteins, noncoding RNAs (ncRNAs) and microRNAs (miRNAs). In this paper, we analyze the miRNA roles in the macrophage polarization at the level of TME and cancerized field in NSCLC. Identifying molecular players that can influence the phenotypic states at the level of malignant cells, tumor microenvironment and cancerized field can provide us new insights into tumor regulatory mechanisms that can be further modulated to restore the immunogenic capacity of the TME. This approach could revert alterations in the cancerized field and could enhance currently available therapy approaches.

scholarly journals Interstitial flow promotes macrophage polarization toward an M2 phenotype

2018 ◽  
Vol 29 (16) ◽  
pp. 1927-1940 ◽  
Author(s):  
Ran Li ◽  
Jean Carlos Serrano ◽  
Hao Xing ◽  
Tara A. Lee ◽  
Hesham Azizgolshani ◽  
...  
Keyword(s):  
Fluid Flow ◽  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cell ◽  
Interstitial Fluid ◽  
Macrophage Polarization ◽  
Interstitial Flow ◽  
Interstitial Fluid Flow ◽  
M2 Polarization ◽  
Tumor Tissues

Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.

scholarly journals Inflammation and Cancer: Extra- and Intracellular Determinants of Tumor-Associated Macrophages as Tumor Promoters

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Gabor J. Szebeni ◽  
Csaba Vizler ◽  
Klara Kitajka ◽  
Laszlo G. Puskas
Keyword(s):  
Tumor Microenvironment ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Therapeutic Interventions ◽  
Tumor Associated Macrophages ◽  
Poor Survival ◽  
Cell Functions ◽  
Intracellular Signals ◽  
Ontogenetic Diversity ◽  
Cell Dissemination

One of the hallmarks of cancer-related inflammation is the recruitment of monocyte-macrophage lineage cells to the tumor microenvironment. These tumor infiltrating myeloid cells are educated by the tumor milieu, rich in cancer cells and stroma components, to exert functions such as promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Our review highlights the ontogenetic diversity of tumor-associated macrophages (TAMs) and describes their main phenotypic markers. We cover fundamental molecular players in the tumor microenvironment including extra- (CCL2, CSF-1, CXCL12, IL-4, IL-13, semaphorins, WNT5A, and WNT7B) and intracellular signals. We discuss how these factors converge on intracellular determinants (STAT3, STAT6, STAT1, NF-κB, RORC1, and HIF-1α) of cell functions and drive the recruitment and polarization of TAMs. Since microRNAs (miRNAs) modulate macrophage polarization key miRNAs (miR-146a, miR-155, miR-125a, miR-511, and miR-223) are also discussed in the context of the inflammatory myeloid tumor compartment. Accumulating evidence suggests that high TAM infiltration correlates with disease progression and overall poor survival of cancer patients. Identification of molecular targets to develop new therapeutic interventions targeting these harmful tumor infiltrating myeloid cells is emerging nowadays.

Genetically-determined influences on the ability of poor responder mice to respond to immunization against Trichuris muris

Parasitology ◽  
1990 ◽  
Vol 100 (3) ◽  
pp. 479-489 ◽  
Author(s):  
K. J. Else ◽  
D. Wakelin
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Primary Infection ◽  
Protective Immunity ◽  
Rapid Development ◽  
Poor Responder ◽  
Post Challenge ◽  
Good Responder ◽  
Trichuris Muris ◽  
Genetically Determined

SUMMARYStrains of mice poorly (B10) or non-responsive (B10.BR) to a primary infection with Trichuris muris were protected against infection by vaccination with excretory/secretory (E/S) antigen in Complete Freund's Adjuvant (CFA). Protection in these mice was slow to be expressed compared to that in good responder strains. Vaccination boosted the IgG and IgG1 antibody responses to E/S antigen and altered the antigen recognition profiles, three high molecular weight antigens (80–85, 90–95, 105–110 kDa) being recognized by antibodies in sera from vaccinated but not control mice. B10. BR mice which had experienced a patent primary infection could not be protected against challenge infections by vaccination and this was correlated with depressed levels of IgG1, but not total IgG, to E'S antigen early post-challenge compared with vaccinated infected mice which had not seen an adult primary infection. There was also lack of recognition of the three high molecular weight antigens recognized by antibodies in sera from mice infected after vaccination. It is suggested that the rapid development of high levels of IgG1 antibodies, and the recognition of the three high molecular weight antigens, may reflect events that are important in protective immunity. Immunomodulation of host immunity by T. muris may therefore be achieved, at least in part, by the suppression of specific IgG1 levels, the production of an irrelevant IgG isotype and prevention of the recognition of critical antigens.

scholarly journals IMAT-IGRT Treatment with Simultaneous Integrated Boost as Dose Escalation for Patients with Cervical Cancer: A Single Institution, Prospective Pilot Study

2021 ◽  
Vol 27 ◽  
Author(s):  
Zoltán Lőcsei ◽  
Klára Sebestyén ◽  
Zsolt Sebestyén ◽  
Eszter Fehér ◽  
Dorottya Soltész ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Total Dose ◽  
Dose Escalation ◽  
Tumor Regression ◽  
Simultaneous Integrated Boost ◽  
Disease Stage ◽  
Mri Scan ◽  
Regression Rate ◽  
Integrated Boost

Purpose: The aim of this study was to introduce the simultaneous integrated boost (SIB) technique to assess the safety of replacement of the brachytherapy (BT) boost for ineligible patients with cervical cancer receiving radiochemotherapy (RCT).Methods: Fourteen patients were enrolled between 2015 and 2018. SIB was delivered using RapidArc technique at doses of 2.4 Gy per fraction during pelvic irradiation with 50.4/1.8 Gy in seven patients (to a total dose of 67.2 Gy) with limited volume disease. In 7 patients with a more advanced disease stage (>5 cm tumor, parametric invasion both sides), parametric boost therapy was added to the pelvic radiotherapy to a total dose of the macroscopic tumor of 79.2 Gy. All patients received simultaneous cisplatin-based chemotherapy for 5 cycles with a dosage of 40 mg/m2. We examined acute toxicity (CTCAE v4.1) and quality of life (EORTC QLQ30 and CX24). The tumor regression rate was evaluated with RECIST 1.1 after the first 3- to 4-months follow-up Magnetic Resonance Imaging (MRI) scan. We calculated the percentage of tumor regression rate and the local control during the follow-up period and evaluated the survival data.Results: Our patient data are presented at a median follow-up time of 24.5 months. During the treatment period, no grade 3 to 4 toxicity was observed. During the follow-up period, no late-onset toxicity was observed. The tumor regression rate at the first MRI scan was 95.31% on average. Disease free survival (DFS) during the median follow-up of 24 months was 98.6%.Conclusion: In patients with cervical cancer, the SIB technique is amenable as part of definitive RCT. Dose escalation with the SIB technique can be safely administered to cervical cancer patients during definitive RCT if BT is not feasible. However, further randomized clinical studies are needed to validate the method, so routine use of it cannot be recommended yet.

NIMG-48. TLR7/8-AGONIST-LOADED NANOPARTICLES REPROGRAM TUMOR-ASSOCIATED MYELOID CELLS FOR EFFECTIVE IMMUNOTHERAPY OF EXPERIMENTAL GLIOMA AND MRI-BASED TREATMENT MONITORING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi139-vi140
Author(s):  
Kira Pfleiderer ◽  
Verena Turco ◽  
Natalie K Horvat ◽  
Jessica Hunger ◽  
Kianush Karimian-Jazi ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Progressive Disease ◽  
Tumor Regression ◽  
Myeloid Cells ◽  
Complete Response ◽  
New Approach ◽  
Splenic Macrophages ◽  
Selective Depletion ◽  
Immunosuppressive Tumor Microenvironment

Abstract Drivers of glioblastoma progression include the immunosuppressive tumor microenvironment (TME), dominated by tumor-associated myeloid cells. Therefore, we investigated a new approach targeting the myeloid compartment to reprogram myeloid cells in the TME using a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the toll-like receptor 7 and 8 (TLR7/8) agonist R848. Biodistribution confirmed specific targeting of CDNP-R848 to tumor-associated macrophages (TAMs) (labeling efficiency: 34.0% ± 22.2%), whereas tumor microglia (5.4% ± 4.4%) and splenic macrophages (13.2% ± 0.7%) revealed less uptake. Interestingly, intravenous application of CDNP-R848 induced strong tumor regression with an overall response rate of 80% (2.5% complete response, 52.5% partial response and 25% stable disease, n=40 mice) in Gl261 syngeneic experimental gliomas, while CDNP vehicle treated animals showed exponential tumor growth (100% progressive disease, n=12 mice). As advanced imaging is essential to monitor intracranial disease and possibly predict response and resistance, we performed high resolution magnetic resonance imaging using ultrasmall iron oxide nanoparticles (USPIO) for macrophage tracking. Increased levels of USPIO uptake in vehicle treated animals compared to CDNP-R848 treated animals were found as an early marker of responding mice (ΔT2*: -11.7 ± 4.2 vs -4.0 ± 2.8 ms, p=0.01). This correlated with an increased influx of myeloid cells into the TME of vehicle treated animals and showed a strong correlation of macrophage recruitment and USPIO uptake (R2: 0.78, p=0.004). Mechanistically, phenotyping of macrophages (CD45high/CD11b+) indicated a pro-inflammatory shift of TAMs with an increased infiltration of pro-inflammatory F4/80+/MHCII+ macrophages during CDNP-R848 treatment. Surprisingly, the anti-tumor effect of CDNP-R848 was independent of CD8+ T cells, CD4+ T cells or NK cells during selective depletion experiments. In summary, this work demonstrates the ability of myeloid-targeted therapies to re-shape the tumor microenvironment for an effective immunotherapy of glioma.

TAMI-19. IMMUNOHISTOLOGICAL ANALYSIS OF ANGIOGENIC FACTORS OTHER THAN VEGF IN GLIOBLASTOMAS IN RELATION TO THE USE OF BEVACIZUMAB

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi202-vi202
Author(s):  
Taketo Ezaki ◽  
Ryota Tamura ◽  
Toshihide Tanaka ◽  
Yuki Kuranari ◽  
Keisuke Miyake ◽  
...  
Keyword(s):  
Growth Factor ◽  
Performance Status ◽  
Progression Free Survival ◽  
Angiogenic Factors ◽  
In Situ Observation ◽  
Newly Diagnosed ◽  
Naive Group ◽  
Paired Samples ◽  
Initial Surgery ◽  
Effective Group

Abstract Although bevacizumab was shown to improve progression-free survival and performance status of the patients with high-grade gliomas, clinical trials consistently showed lack of benefit in terms of patients’ overall survival. The recurrent tumors are inevitably more aggressive and invasive as compared with the original tumors, and the in-situ observation in actual human specimens is essential to elucidate the mechanism of resistance. In Japan, bevacizumab was approved not only for recurrent but also for newly diagnosed cases. The safety as well as efficacy of resection following neoadjuvant bevacizumab has been reported, and a phase II study is currently ongoing (UMIN-000025579). In the present study, the expression of angiogenic factors other than VEGF (basic fibroblast growth factor (bFGF), placenral growth factor (PlGF), angiopoietin1/2 and ephrinA2) was investigated by immunohistochemistry to be compared among tumors with no previous bevacizumab treatment, those resected following bevacizumab, and those refractory to bevacizumab. Fifty-nine samples from 42 patients were included; 24 of newly diagnosed glioblastomas with no previous bevacizumab (naïve group), 16 resected following neoadjuvant bevacizumab (effective group), and 6 resected after recurrence or autopsied (refractory/autopsied group). 12 were paired samples (8 naïve and refractory, 4 effective and refractory). The expression of PlGF significantly increased in the effective group as compared with the naïve group (p=0.003). In the paired specimens, there was a trend towards increased expression of PlGF in the second specimens (refractory/autopsied group) as compared with the specimens of initial surgery (p=0.083). Angiopoietin1, angiopoietin2 and ephrinA2 were characteristically expressed in the microvessels less than 15μm. The increased expression of PlGF might be associated with the recurrence after bevacizumab.

scholarly journals Thioholgamide A, a New Anti-Proliferative Anti-Tumor Agent, Modulates Macrophage Polarization and Metabolism

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1288 ◽  
Author(s):  
Charlotte Dahlem ◽  
Wei Xiong Siow ◽  
Maria Lopatniuk ◽  
William K. F. Tse ◽  
Sonja M. Kessler ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cell Metabolism ◽  
Macrophage Polarization ◽  
Human Monocyte ◽  
Live Cell ◽  
Hallmarks Of Cancer ◽  
Culture Models

Natural products represent powerful tools searching for novel anticancer drugs. Thioholgamide A (thioA) is a ribosomally synthesized and post-translationally modified peptide, which has been identified as a product of Streptomyces sp. MUSC 136T. In this study, we provide a comprehensive biological profile of thioA, elucidating its effects on different hallmarks of cancer in tumor cells as well as in macrophages as crucial players of the tumor microenvironment. In 2D and 3D in vitro cell culture models thioA showed potent anti-proliferative activities in cancer cells at nanomolar concentrations. Anti-proliferative actions were confirmed in vivo in zebrafish embryos. Cytotoxicity was only induced at several-fold higher concentrations, as assessed by live-cell microscopy and biochemical analyses. ThioA exhibited a potent modulation of cell metabolism by inhibiting oxidative phosphorylation, as determined in a live-cell metabolic assay platform. The metabolic modulation caused a repolarization of in vitro differentiated and polarized tumor-promoting human monocyte-derived macrophages: ThioA-treated macrophages showed an altered morphology and a modulated expression of genes and surface markers. Taken together, the metabolic regulator thioA revealed low activities in non-tumorigenic cells and an interesting anti-cancer profile by orchestrating different hallmarks of cancer, both in tumor cells as well as in macrophages as part of the tumor microenvironment.

Expression pattern and prognostic significance of myosin light chain 9 (MYL9): a novel biomarker in glioblastoma

2019 ◽  
Vol 72 (10) ◽  
pp. 677-681 ◽  
Author(s):  
Banavathy S Kruthika ◽  
Harsha Sugur ◽  
Kanuri Nandaki ◽  
Arivazhagan Arimappamagan ◽  
Kondaiah Paturu ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Newly Diagnosed ◽  
Paired Samples ◽  
Idh1 R132h ◽  
Recurrent Gbm

AimsTumour recurrence is inevitable in glioblastoma (GBM) and mostly noted in the peritumoural brain zone (PT). In our previous microarray-based study, we identified Myosin Light Chain 9 (MYL9) as a highly expressed gene in the PT of GBM. Therefore, we aimed to study the expression pattern and clinical significance of MYL9 in GBM.MethodsPatient samples included three retrospective cohorts: 25 GBM cases with differential biopsies of tumour core and PT, 62 retrospective cases of newly diagnosed GBM with survival information and 20 paired samples (newly diagnosed and recurrent GBM). All tumour tissues, archived as formalin fixed paraffin embedded blocks were retrieved and immunohistochemistry for MYL9 and IDH1 R132H was performed. MYL9 expression was correlated with patient prognosis in our cohort and in The Cancer Genome Atlas (TCGA) and Rembrandt cohorts. It was further evaluated in the 20 paired samples of GBM.ResultsMYL9 showed a cytoplasmic membranous staining of tumour cells. The staining pattern was variable and patchy within tumours. Higher MYL9 expression was associated with poor overall and progression-free survival in our and in TCGA and Rembrandt cohorts. The expression of MYL9 was higher in IDH1 R132H immunonegative cases.ConclusionsWe show MYL9 as a novel biomarker, variably expressed in GBM. The association of high MYL9 expression with poor prognosis in newly diagnosed GBM patients and increased expression in recurrent GBM is indicative of its role in conferring tumour aggressiveness.

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