Non-genetic engineering of cytotoxic T cells to target IL-4 receptor enhances tumor homing and therapeutic efficacy against melanoma

Gunassekaran, Gowri Rangaswamy; Hong, Chae Moon; Vadevoo, Sri Murugan Poongkavithai; Chi, Lianhua; Padmanaban, Guruprasath; Ahn, Bierng-Chearl; Kim, Ha-Jeong; Kang, Tae Heung; Lee, Byungheon

doi:10.1016/j.biomaterials.2018.01.013

Cited by 15 publications

(10 citation statements)

References 52 publications

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“…Interestingly, an IL‐4R binding peptide (IL4RPep‐1) conjugated CTLs caused rapid and robust reprogramming of M2 type macrophages to M1 phenotype with lower IL‐10 and higher IL‐6. [ 60 ] The IL‐4R targeted CTLs exhibited enhanced tumor homing ability and reversed the immunosuppressive TME to improve the immunotherapy against melanoma.…”

Section: Nanomedicine Mediated Tams Targeting To Promote Their Re‐edumentioning

confidence: 99%

Reprogramming Tumor Associated Macrophages toward M1 Phenotypes with Nanomedicine for Anticancer Immunotherapy

Gong

et al. 2020

Advanced Therapeutics

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Tumor-associated macrophages (TAMs), one of the most important constituents in tumor immunosuppressive microenvironments, are a potential therapeutic target due to their essential role in promoting tumor progression and metastasis. Macrophages are usually divided into two categories of protumoral M2-like TAMs and antitumoral M1 phenotypes at the two extremes. Reprogramming M2-like TAMs toward tumoricidal M1 phenotype is especially intriguing in terms of the restoration of antitumor immunity for anticancer immunotherapy. In this review, the recent advances of nanomedicine-mediated reprogramming of TAMs from M2 to M1 to elicit the antitumor immunity are discussed. This reprogramming can be achieved via direct re-education by targeted delivery of various active agents to TAMs and indirect re-education by modulating the abnormal tumor microenvironment. Perspectives on nanomedicine mediated TAMs-M1 reprogramming for effective anticancer immunotherapy are also presented.

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Section: Nanomedicine Mediated Tams Targeting To Promote Their Re‐edumentioning

confidence: 99%

Reprogramming Tumor Associated Macrophages toward M1 Phenotypes with Nanomedicine for Anticancer Immunotherapy

Gong

et al. 2020

Advanced Therapeutics

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“…The non-specific transfer of EVs to other organs can be modulated by surface engineering, and tumors can be specifically targeted by adding targeting peptides or proteins to the EVs. 31,33 Recently, EVs have been investigated more as drug delivery vehicles. 8 EVs enriched with NIS protein can also be used to transfer anti-cancer drugs, which could further improve cancer therapies.…”

Section: Discussionmentioning

confidence: 99%

<p>A novel strategy of transferring NIS protein to cells using extracellular vesicles leads to increase in iodine uptake and cytotoxicity</p>

Son¹,

Gangadaran²,

Ahn³

2019

IJN

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Background: This study was designed to explore a novel approach for transferring NIS protein to cells using extracellular vesicle (EV) and enhancing iodine avidity in hepatocellular carcinoma (HCC) cells. Methods: We transfected the HCC cells (Huh7) with NIS gene, designated as Huh7/NIS, and isolated the EVs from them. Presence of NIS protein in EVs and EV-mediated transport of NIS protein to recipient Huh7 cells were tested using Western blotting. We also examined radioiodine uptake in Huh7 cells treated with EV-Huh7/NIS. Results: Successful transfer of NIS protein into Huh7 cells was confirmed by WB and microscopy. EVs showed high levels of NIS protein in them. Treatment of Huh7 cells with EV-Huh7/ NIS increased the NIS protein level and enhanced 125 I uptake in recipient Huh7 cells. In addition, EV-huh7/NIS pre-treatment enhanced the cytotoxicity of 131 I therapy against Huh7 cells by inducing increased DNA damage/increased γH2A.X foci formation. Conclusion: This is the first-of-its-kind demonstration of successful transportation of the NIS protein to cells via EVs, which increased radioiodine uptake. This approach can revert radioiodine-resistant cancers into radioiodine-sensitive cancers.

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“…RBC-EMs shown to have short-circulation time, which can be changed by various methodologies such as, a blocking of scavenger receptor class A (SR-A) as a monocyte/macrophage uptake receptor for exosomes. In vivo blockade of SR-A with dextran sulfate dramatically decreased exosome liver clearance in mice, while enhancing tumor accumulation ( Watson et al, 2016 ; Zhu et al, 2018 ); macrophage-depletion by clodronate in mice shown to improve the longer circulation time and slower clearance in vivo ( Imai et al, 2015 ); Recently, tumor-targeting peptides have been used to target tumors with cytotoxic T cells or anti-apoptotic peptides to inhibit the tumor in vivo ( Sarangthem et al, 2016 ; Gunassekaran et al, 2018 ), and another report has shown that exosomes labeled with cardiac homing peptides can be used to target myocardial infarction in vivo ( Vandergriff et al, 2018 ). Such a targeting approach can be used to direct the RBC-EMs to the target site with therapeutic drugs loaded in them, and the RBC-EMs containing therapeutic drugs can be feasibly monitored in vivo by 99m Tc labeling which can accelerate development of the drug delivery system in clinics.…”

Section: Discussionmentioning

confidence: 99%

In vivo Non-invasive Imaging of Radio-Labeled Exosome-Mimetics Derived From Red Blood Cells in Mice

Gangadaran

Hong

et al. 2018

Front. Pharmacol.

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Exosomes are natural nano-sized membrane vesicles that have garnered recent interest owing to their potential as drug delivery vehicles. Though exosomes are effective drug carriers, their production and in vivo biodistribution are still not completely elucidated. We analyzed the production of exosome mimetics (EMs) from red blood cells (RBCs) and the radio-labeling of the RBC-EMs for in vivo imaging. Engineered EMs from RBCs were produced in large-scale by a one-step extrusion method, and further purified by density-gradient centrifugation. RBC-EMs were labeled with technetium-99m (99mTc). For non-invasive imaging, 99mTc (free) or 99mTc-RBC-EMs were injected in mice, and their biodistribution was analyzed by gamma camera imaging. Animals were sacrificed, and organs were collected for further biodistribution analysis. RBC-EMs have similar characteristics as the RBC exosomes but have a 130-fold higher production yield in terms of particle numbers. Radiochemical purity of 99mTc-RBC-EMs was almost 100% till 2 h reduced to 97% at 3 h. Radio-labeling did not affect the size and morphology of RBC-EMs. In contrast to free 99mTc, in vivo imaging of 99mTc-RBC-EMs in mice showed higher uptake in the liver and spleen, and no uptake in the thyroid. Ex vivo imaging confirmed the in vivo findings. Furthermore, fluorescent imaging confirmed the nuclear imaging findings. Immunofluorescent imaging revealed that the hepatic uptake of RBC-EMs was significantly mediated by kupffer cells (resident hepatic macrophages). Our results demonstrate a simple yet large-scale production method for a novel type of RBC-EMs, which can be effectively labeled with 99mTc, and feasibly monitored in vivo by nuclear imaging. The RBC-EMs may be used as in vivo drug delivery vehicles.

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Non-genetic engineering of cytotoxic T cells to target IL-4 receptor enhances tumor homing and therapeutic efficacy against melanoma

Cited by 15 publications

References 52 publications

Reprogramming Tumor Associated Macrophages toward M1 Phenotypes with Nanomedicine for Anticancer Immunotherapy

Reprogramming Tumor Associated Macrophages toward M1 Phenotypes with Nanomedicine for Anticancer Immunotherapy

<p>A novel strategy of transferring NIS protein to cells using extracellular vesicles leads to increase in iodine uptake and cytotoxicity</p>

In vivo Non-invasive Imaging of Radio-Labeled Exosome-Mimetics Derived From Red Blood Cells in Mice

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