A biomimetic nanozyme/camptothecin hybrid system for synergistically enhanced radiotherapy

2020 ◽  
Vol 8 (24) ◽  
pp. 5312-5319 ◽  
Author(s):  
Daoming Zhu ◽  
Meng Lyu ◽  
Wei Jiang ◽  
Meng Suo ◽  
Qinqin Huang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Hybrid System ◽  
Therapeutic Regimen ◽  
Hypoxic Tumor

Although radiotherapy (RT) has been an effective therapeutic regimen for regulating most solid tumors, its effect is limited by the hypoxic tumor microenvironment and radio-tolerance of tumor cells to a large extent.

Oxygen-producing proenzyme hydrogels for photodynamic mediated metastasis-inhibited combinational therapy

2021 ◽  
Author(s):  
Jiansheng Liu ◽  
Xueqin Qing ◽  
Qin Zhang ◽  
Ningyue Yu ◽  
Mengbin Ding ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Therapeutic Efficacy ◽  
Tumor Metastasis ◽  
Combinational Therapy ◽  
Hypoxic Tumor

Photodynamic therapy (PDT) has provided a promising approach for treatment of solid tumors, while the therapeutic efficacy is often limited due to hypoxic tumor microenvironment, resulting in tumor metastasis. We...

scholarly journals P09.05 Plasma CD27, a surrogate of intratumoral CD27-CD70 interaction, correlates with immunotherapy resistance in renal cancer

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A30.1-A30
Author(s):  
N Benhamouda ◽  
I Sam ◽  
N Epaillard ◽  
A Gey ◽  
A Saldmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Principal Investigator ◽  
Cell Phenotype ◽  
Metastatic Rcc ◽  
Research Grant

BackgroundCD70, a costimulatory molecule on antigen presenting cells, is known to activate CD27-expressing T cells. CD27-CD70 interaction leads to the release of soluble CD27 (sCD27). However, persistent interaction of CD27 and CD70 such as in chronic infection may exhaust the T cell pool and promote apoptosis. Surprisingly, our analysis based on TCGA database show that clear cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors. Despite the important clinical efficacy of immunotherapy by anti-PD-1 in RCC patients, the overall response to anti-PD1 remains modest. The relationship between the CD27-CD70 interaction in the RCC and the response to immunotherapy is still unclear.Materials and MethodsTo study the CD27 and CD70 expression in the tumor microenvironment (TME), FFPE tumor tissues from 25 RCC patients were analysed using multiplex in situ immunofluorescence. 10 fresh RCC tumor samples were collected to analyse the phenotype of CD27+ T cells by flow cytometry and 4 samples were proceeded for single-cell RNA-seq analysis. A cohort of metastatic RCC patients (n = 35) treated by anti-PD-1 were enrolled for the measurement of plasma sCD27 by ELISA and the survival analysis is also realized.ResultsIn the TME, we demonstrated that CD27+ T cells interact with CD70-expressing tumor cells. In fresh tumors from RCC patients, CD27+ T cells express higher levels of cleaved caspase 3 (a classical marker of apoptosis) than CD27- T cells. We confirmed the apoptotic signature (BAX, FASLG, BCL2L11, CYCS, FBXO32, LGALS1, PIK3R1, TERF1, TXNIP, CDKN2A) of CD27+ T cells by single-cell RNAseq analysis. CD27+T cells also had a tissue resident memory T cell phenotype with enriched gene expression of ITGAE, PRDM1, RBPJ and ZNF683. Moreover, CD27+T cells display an exhaustion phenotype with the expression of multiple inhibitory receptors gene signature (PDCD1, CTLA4, HAVCR2, LAG3, etc). Besides, intratumoral CD27-CD70 interaction significantly correlates with plasma sCD27 concentration in RCC (p = 0.0017). In metastatic RCC patients treated with anti-PD-1, higher levels of sCD27 predict poor overall survival (p = 0.037), while it did not correlate with inflammatory markers or clinical prognostic criteria.ConclusionsIn conclusion, we demonstrated that sCD27, a surrogate of T cell dysfunction in tumors likely induced by persistent interactions of CD27+T cells and CD70-expressing tumor cells, is a predictive biomarker of resistance to immunotherapy in mRCC. To our knowledge, this is the first report showing that a peripheral blood biomarker may reflect certain aspects of the tumor-host interaction in the tumor microenvironment. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be further extended to other types of tumors. CD70-CD27 interaction could thus be considered as a mechanism of tumor escape, but also a novel therapeutic target in cancers.Disclosure InformationN. Benhamouda: None. I. Sam: None. N. Epaillard: None. A. Gey: None. A. Saldmann: None. J. Pineau: None. M. Hasan: None. V. Verkarre: None. V. Libri: None. S. Mella: None. C. Granier: None. C. Broudin: None. P. Ravel: None. B. Jabla: None. N. Chaput: None. L. Albiges: None. Y. Vano: None. O. Adotevi: None. S. Oudard: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; SIRIC CARPEM, FONCER. E. Tartour: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Fondation ARC, INCA PLBio, Labex Immuno-Oncology, SIRIC CARPEM, FONCER, IDEX université de Paris, Inserm Transfert.

scholarly journals 799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A834-A834
Author(s):  
Xue Yao ◽  
Sandro Matosevic
Keyword(s):  
Tumor Microenvironment ◽  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Nk Cell Therapy

BackgroundThe effectiveness of natural killer (NK) cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment (TME). Glioblastoma multiforme (GBM) is one such heavily immunosuppressive tumor that has been particularly hard to target and remains without a viable treatment. The development of novel approaches to enhance the efficacy of NK cells against GBM is urgently needed. NK cell engagers (NKCE) have been developed to enhance the efficacy of NK cell therapy.MethodsTo improve the clinical efficacy of NK cell therapy, we are developing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains. Neoantigens are new antigens formed specifically in tumor cells due to genome mutations, making them highly specific tools to target tumor cells. Our engager has been designed to target Wilms' tumor-1 (WT-1), a highly specific antigen overexpressed in GBM among other solid tumors. This is done through the generation of an scFv specific targeting the complex of WT-1126-134/HLA-A*02:01 on the surface of GBM. On the NK cell side, the engager is designed to target the activating receptor NKp46. Incorporation of the cytokine IL-15 within the engager supports the maturation, persistence, and expansion of NK cells in vivo while favoring their proliferation and survival in the tumor microenvironment. Additionally, our data indicated that the chemokine CXCL10 plays an important role in the infiltration of NK cells into GBM, however, GBM tumors produce low levels of this chemokine. Incorporation of a CXCL10-producing function into our engager supports intratumoral NK cell trafficking by promoting, through their synthetic production, increased levels of CXCL10 locally in the tumor microenvironment.ResultsCollectively, this has resulted in a novel multifunctional NK cell engager, combining neoantigen-cytokine-chemokine elements fused to an activating domain-specific to NK cells, and we have investigated its ability to support and enhance NK cell-mediated cytotoxicity against solid tumors in vitro and in vivo against patient-derived GBM models. The multi-specific engager shows both high tumor specificity, as well as the ability to overcome NK cell dysfunction encountered in the GBM TME.ConclusionsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit superior ex vivo expansion, infiltration, and antitumor activity in the treatment of GBM and other solid tumors.

scholarly journals Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1539 ◽  
Author(s):  
Peter Ping Lin
Keyword(s):  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Mesenchymal Transition ◽  
Tumor Neovascularization ◽  
Hypoxic Tumor

Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.

scholarly journals Anti-Tumor Responses By Ibrutinib and Anti-PD-1 Blockade Is Enhanced By Phosphatidylserine-Targeting Antibody Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5379-5379
Author(s):  
Jian Gong ◽  
Michael Gray ◽  
Jeff Hutchins ◽  
Bruce Freimark
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Immune System ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
B Cell ◽  
Cell Line ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Triple Negative

Abstract Introduction: Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane that becomes exposed on vascular endothelial cells and tumor cells in the tumor microenvironment, particularly in response to chemotherapy and irradiation. Binding of antibodies targeting PS on the tumor endothelial cells and tumors induces the recruitment of immune cells and engages the immune system to destroy tumor and associated vasculature and by blocking the immunosuppressive action of PS. Recent studies have demonstrated that PS-targeting antibodies enhance the anti-tumor activity of immune checkpoint antibody blockade to CTLA-4 and PD-1 in mouse breast and melanoma tumor models (Freimark et al. Cancer Immunol. Res. 2016; Gray et al. Breast Cancer Res 2016). Ibrutinib is an approved anticancer drug targeting B-cell malignancies that is a selective, covalent inhibitor of the enzyme Bruton's tyrosine kinase(BTK) in B-cell tumors. Data from recent mouse tumor studies demonstrate that ibrutinib in combination with anti-PD-1 antibody blockade inhibits growth of solid tumors (lacking BTK expression) suggesting that ibrutinib may inhibit kinases of the immune system such as interleukin-2 inducible T-cell kinase (ITK), to enhance specific anti-tumor responses (Sagiv-Barfli et al. PNAS 20 2015). Methods: The present study was conducted to evaluate the anti-tumor effects of combination therapy including PS-targeting antibody mouse chimeric 1N11 (mch1N11), ibrutinib (32765) and anti-PD-1 antibody using C57BL/6 mice bearing triple negative E0771 breast tumors. Tumors were staged to an initial volume of ~100mm3and randomized to treatment groups (N=10) with mch1N11 or isotype at 10 mg/kg qw, anti-PD-1 at 2.5 mg/kg qw or ibrunitib 6 mg/kg or vehicle qd x 8. Tumor volumes were measured twice per week to determine tumor growth inhibition (TGI) relative to control treated animals until a maximum volume of 1500-2000mm3. The in vitro sensitivity of E0771 tumor cells to ibrutinib was compared to drug sensitive Jeko-1 lymphoma cells in a 72 hour growth and viability assay. Results: The E0771 cell line is resistant in vitroto 10 mM ibrutinib compared to the drug-sensitive Jeko-1 cell line (Figure 1). Mice bearing E0771 tumors treated with mch1N11, ibrutinib and anti-PD-1 alone had 22.2%, 23.5% and 32.6% TGI respectively. Combination of two agents increased the TGI for mch1N11 and ibrutinib to 30.5%, ibrutinib and anti-PD-1 to 34.5%, mch1N11 and anti-PD-1 to 36.1%. A triple combination therapy had statistically greater TGI compared to control treated mice (59.9%, p = 0.0084) and was greater than single and double combination therapies. Conclusion:Treatment of solid tumors with a combination of inhibitors that target PS, ITK and the PD-1/PD-L1 axis in the tumor microenvironment provides a novel treatment for solid tumors, including triple negative breast cancer. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Gong: Peregrine Pharmaceuticals, Inc.: Employment. Gray:Peregrine Pharmaceuticals, Inc.: Employment. Hutchins:Peregrine Pharmaceuticals, Inc.: Employment. Freimark:Peregrine Pharmaceuticals, Inc.: Employment.

scholarly journals A Tumor Microenvironment-Responsive Poly(amidoamine) Dendrimer Nanoplatform for Hypoxia-Responsive Chemo/Chemodynamic Therapy

2021 ◽  
Author(s):  
Yingchao Hao ◽  
Yue Gao ◽  
Yu Fan ◽  
Changchang Zhang ◽  
Mengsi Zhan ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Breast Cancer Cells ◽  
Tumor Metastasis ◽  
Phenylboronic Acid ◽  
Pamam Dendrimers ◽  
Synergistic Inhibition ◽  
Catalytic Metal ◽  
Hypoxic Tumor ◽  
Tumor Types

Abstract Background: Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, since toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction at the tumor microenvironment (TME) with low pH and high endogenous hydrogen peroxide (H2O2). However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict its curative outcomes.Results: In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) with good stability could be specifically accumulated at tumors, efficiently taken up by tumor cells overexpressing sialic acid residues, and release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro and in vivo experiments using murine breast cancer cells (4T1) demonstrated that the GPPCT nanoplatform could efficiently generate toxic ·OH in tumor cells while simultaneously deplete GSH, effectively kill hypoxic tumor cells by activated TPZ radicals, reduce tumor metastasis, and show no significant systemic toxicity.Conclusions: The targeted GPPCT nanoplatform may be developed for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.

scholarly journals A GdW10@PDA-CAT Sensitizer with High-Z Effect and Self-Supplied Oxygen for Hypoxic-Tumor Radiotherapy

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 128
Author(s):  
Lixia Chen ◽  
Yang Zhang ◽  
Xinming Zhang ◽  
Ruijuan Lv ◽  
Rongtian Sheng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
X Ray ◽  
Cells In Culture ◽  
Ht29 Cells ◽  
Radiotherapy Field ◽  
Anticancer Treatment ◽  
Hypoxic Tumor

Anticancer treatment is largely affected by the hypoxic tumor microenvironment (TME), which causes the resistance of the tumor to radiotherapy. Combining radiosensitizer compounds and O2 self-enriched moieties is an emerging strategy in hypoxic-tumor treatments. Herein, we engineered GdW10@PDA-CAT (K3Na4H2GdW10O36·2H2O, GdW10, polydopamine, PDA, catalase, CAT) composites as a radiosensitizer for the TME-manipulated enhancement of radiotherapy. In the composites, Gd (Z = 64) and W (Z = 74), as the high Z elements, make X-ray gather in tumor cells, thereby enhancing DNA damage induced by radiation. CAT can convert H2O2 to O2 and H2O to enhance the X-ray effect under hypoxic TME. CAT and PDA modification enhances the biocompatibility of the composites. Our results showed that GdW10@PDA-CAT composites increased the efficiency of radiotherapy in HT29 cells in culture. This polyoxometalates and O2 self-supplement composites provide a promising radiosensitizer for the radiotherapy field.

scholarly journals The control of acidity in tumor cells: a biophysical model

2020 ◽  
Author(s):  
Nicola Piasentin ◽  
Edoardo Milotti ◽  
Roberto Chignola
Keyword(s):  
Experimental Data ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Biophysical Model ◽  
Tumor Aggressiveness ◽  
Surrounding Environment ◽  
Carbonic Anhydrase 9 ◽  
Independent Experimental Data ◽  
Dynamic Interplay

ABSTRACTAcidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. The model takes into account the dynamic interplay between glucose and O2 consumption with lactate and CO2 production and connects these processes to H+ and fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. The simulations show a dominance of the H+ exchanges in well-oxygenated regions, and of exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. The model also includes the activity of the enzyme Carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear pHi equalizer at any O2 level in cells that grow in acidic extracellular environments.SIGNIFICANCEThe activity of cancer cells in solid tumors affects the surrounding environment in many ways, and an elevated acidity is a common feature of the tumor microenvironment. In this paper we propose a model of intracellular/extracellular acidity that is linked to cellular metabolism and includes all the main molecular players. The model is reliable, robust and validated with experimental data and can be used as an essential building block of more comprehensive in silico research on solid tumors.

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