Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy

Hyunjoon Kim; Lin Niu; Peter Larson; Tamara A. Kucaba; Katherine A. Murphy; Britnie R. James; David M Ferguson; Thomas S Griffith; Jayanth Panyam

doi:10.1016/j.biomaterials.2018.02.034

Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy

Hyunjoon Kim, Lin Niu, Peter Larson, Tamara A. Kucaba, Katherine A. Murphy, Britnie R. James, David M Ferguson, Thomas S Griffith, Jayanth Panyam

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

Abstract

Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds. Encapsulation of these TLR 7/8 agonists in poly(lactide-co-glycolide) (PLGA) nanoparticles increased the co-stimulatory molecule expression and antigen presentation via MHC I by DCs compared to the soluble agonist. When administered subcutaneously, these nanoparticles migrated to draining lymph node and triggered DC activation and expansion. This lead to expansion of antigen-specific CD8 T cells and enhanced CTL response, which resulted in significant prophylactic and therapeutic efficacy in melanoma, bladder and renal cell carcinoma tumor models. Importantly, our studies demonstrate significant reductions in systemic metastasis with the nanoparticle vaccine. Our results suggest novel TLR 7/8 agonist-encapsulated nanoparticles are potent immunostimulatory adjuvants for cancer immunotherapy.

Original language	English (US)
Pages (from-to)	38-53
Number of pages	16
Journal	Biomaterials
Volume	164
DOIs	https://doi.org/10.1016/j.biomaterials.2018.02.034
State	Published - May 2018

Bibliographical note

Funding Information:
We thank John Oja and Guillermo Marques in the University Imaging Centers (University of Minnesota) for confocal microscopy training. TEM and SEM imaging was performed with the assistance of Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from NSF through the MRSEC program. This work was supported by the Grant in aid program, University of Minnesota (J.P.), GAP award (J.P.), Masonic Cancer Center, University of Minnesota (T.S.G.), the Prostate and Urological Cancer Translational Working Group (T.S.G.), and the Randy Shaver Cancer Research & Community Fund (J.P., T.S.G., D.M.F.)

Funding Information:
We thank John Oja and Guillermo Marques in the University Imaging Centers (University of Minnesota) for confocal microscopy training. TEM and SEM imaging was performed with the assistance of Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from NSF through the MRSEC program. This work was supported by the Grant in aid program, University of Minnesota (J.P.), GAP award (J.P.), Masonic Cancer Center, University of Minnesota (T.S.G.), the Prostate and Urological Cancer Translational Working Group (T.S.G.), and the Randy Shaver Cancer Research & Community Fund (J.P., T.S.G., D.M.F.)

Publisher Copyright:
© 2018

Keywords

Cancer vaccine
Immunotherapy
Nanoparticle
TLR7/8 agonist

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.biomaterials.2018.02.034

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@article{64853760aae942a590b8bf12ed88b938,

title = "Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy",

abstract = "Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds. Encapsulation of these TLR 7/8 agonists in poly(lactide-co-glycolide) (PLGA) nanoparticles increased the co-stimulatory molecule expression and antigen presentation via MHC I by DCs compared to the soluble agonist. When administered subcutaneously, these nanoparticles migrated to draining lymph node and triggered DC activation and expansion. This lead to expansion of antigen-specific CD8 T cells and enhanced CTL response, which resulted in significant prophylactic and therapeutic efficacy in melanoma, bladder and renal cell carcinoma tumor models. Importantly, our studies demonstrate significant reductions in systemic metastasis with the nanoparticle vaccine. Our results suggest novel TLR 7/8 agonist-encapsulated nanoparticles are potent immunostimulatory adjuvants for cancer immunotherapy.",

keywords = "Cancer vaccine, Immunotherapy, Nanoparticle, TLR7/8 agonist",

author = "Hyunjoon Kim and Lin Niu and Peter Larson and Kucaba, {Tamara A.} and Murphy, {Katherine A.} and James, {Britnie R.} and Ferguson, {David M} and Griffith, {Thomas S} and Jayanth Panyam",

note = "Funding Information: We thank John Oja and Guillermo Marques in the University Imaging Centers (University of Minnesota) for confocal microscopy training. TEM and SEM imaging was performed with the assistance of Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from NSF through the MRSEC program. This work was supported by the Grant in aid program, University of Minnesota (J.P.), GAP award (J.P.), Masonic Cancer Center, University of Minnesota (T.S.G.), the Prostate and Urological Cancer Translational Working Group (T.S.G.), and the Randy Shaver Cancer Research & Community Fund (J.P., T.S.G., D.M.F.) Funding Information: We thank John Oja and Guillermo Marques in the University Imaging Centers (University of Minnesota) for confocal microscopy training. TEM and SEM imaging was performed with the assistance of Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from NSF through the MRSEC program. This work was supported by the Grant in aid program, University of Minnesota (J.P.), GAP award (J.P.), Masonic Cancer Center, University of Minnesota (T.S.G.), the Prostate and Urological Cancer Translational Working Group (T.S.G.), and the Randy Shaver Cancer Research & Community Fund (J.P., T.S.G., D.M.F.) Publisher Copyright: {\textcopyright} 2018",

year = "2018",

month = may,

doi = "10.1016/j.biomaterials.2018.02.034",

language = "English (US)",

volume = "164",

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journal = "Biomaterials",

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T1 - Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy

AU - Kim, Hyunjoon

AU - Niu, Lin

AU - Larson, Peter

AU - Kucaba, Tamara A.

AU - Murphy, Katherine A.

AU - James, Britnie R.

AU - Ferguson, David M

AU - Griffith, Thomas S

AU - Panyam, Jayanth

N1 - Funding Information: We thank John Oja and Guillermo Marques in the University Imaging Centers (University of Minnesota) for confocal microscopy training. TEM and SEM imaging was performed with the assistance of Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from NSF through the MRSEC program. This work was supported by the Grant in aid program, University of Minnesota (J.P.), GAP award (J.P.), Masonic Cancer Center, University of Minnesota (T.S.G.), the Prostate and Urological Cancer Translational Working Group (T.S.G.), and the Randy Shaver Cancer Research & Community Fund (J.P., T.S.G., D.M.F.) Funding Information: We thank John Oja and Guillermo Marques in the University Imaging Centers (University of Minnesota) for confocal microscopy training. TEM and SEM imaging was performed with the assistance of Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from NSF through the MRSEC program. This work was supported by the Grant in aid program, University of Minnesota (J.P.), GAP award (J.P.), Masonic Cancer Center, University of Minnesota (T.S.G.), the Prostate and Urological Cancer Translational Working Group (T.S.G.), and the Randy Shaver Cancer Research & Community Fund (J.P., T.S.G., D.M.F.) Publisher Copyright: © 2018

PY - 2018/5

Y1 - 2018/5

N2 - Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds. Encapsulation of these TLR 7/8 agonists in poly(lactide-co-glycolide) (PLGA) nanoparticles increased the co-stimulatory molecule expression and antigen presentation via MHC I by DCs compared to the soluble agonist. When administered subcutaneously, these nanoparticles migrated to draining lymph node and triggered DC activation and expansion. This lead to expansion of antigen-specific CD8 T cells and enhanced CTL response, which resulted in significant prophylactic and therapeutic efficacy in melanoma, bladder and renal cell carcinoma tumor models. Importantly, our studies demonstrate significant reductions in systemic metastasis with the nanoparticle vaccine. Our results suggest novel TLR 7/8 agonist-encapsulated nanoparticles are potent immunostimulatory adjuvants for cancer immunotherapy.

AB - Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds. Encapsulation of these TLR 7/8 agonists in poly(lactide-co-glycolide) (PLGA) nanoparticles increased the co-stimulatory molecule expression and antigen presentation via MHC I by DCs compared to the soluble agonist. When administered subcutaneously, these nanoparticles migrated to draining lymph node and triggered DC activation and expansion. This lead to expansion of antigen-specific CD8 T cells and enhanced CTL response, which resulted in significant prophylactic and therapeutic efficacy in melanoma, bladder and renal cell carcinoma tumor models. Importantly, our studies demonstrate significant reductions in systemic metastasis with the nanoparticle vaccine. Our results suggest novel TLR 7/8 agonist-encapsulated nanoparticles are potent immunostimulatory adjuvants for cancer immunotherapy.

KW - Cancer vaccine

KW - Immunotherapy

KW - Nanoparticle

KW - TLR7/8 agonist

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JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

ER -

Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy

Abstract

Bibliographical note

Keywords

UN SDGs

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Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

University Assets

Olympus Fluoview FV1000 BX2 Upright Confocal

Olympus Fluoview FV1000 IX2 Inverted Confocal with FLIM Detector

University Imaging Centers

Cite this