Therapeutic efficacy of cancer vaccine adjuvanted with nanoemulsion loaded with TLR7/8 agonist in lung cancer model

doi:10.1016/j.nano.2021.102415

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 37, October 2021, 102415

https://doi.org/10.1016/j.nano.2021.102415 Get rights and content

Abstract

Although immune checkpoint inhibitors have significantly improved clinical outcomes in various malignant cancers, only a small proportion of patients reap benefits, likely due to the low number of T cells and high number of immunosuppressive cells in the tumor microenvironment (TME) of patients with advanced disease. We developed a cancer vaccine adjuvanted with nanoemulsion (NE) loaded with TLR7/8 agonist (R848) and analyzed its therapeutic effect alone or in combination with immune checkpoint inhibitors, on antitumor immune responses and the reprogramming of suppressive immune cells in the TME. NE (R848) demonstrated robust local and systemic antitumor immune responses in both subcutaneous and orthotopic mouse lung cancer models, inducing tumor-specific T cell activation and mitigating T cell exhaustion. Combination with anti-PD-1 antibodies showed synergistic effects with respect to therapeutic efficacy and survival rate. Thus, NE (R848)-based cancer vaccines could prevent tumor recurrence and prolong survival by activating antitumor immunity and reprogramming immunosuppression.

Graphical Abstract

Schematic illustration of the cancer immunotherapy based on cancer vaccines adjuvanted with nanoemulsion (NE) loaded with a TLR7/8 agonist (R848) (NE [R848]) in subcutaneous and orthotopic mouse lung cancer models. NE (R848) stimulates dendritic cells (DCs), proliferates T cells, and converts pro-tumoral immune cells into antitumoral ones, resulting in synergistic antitumor immune responses with immune checkpoint inhibitors (anti-programmed-death-1 [anti-PD-1]).

Section snippets

Cell culture and animals

The ASB-XIV murine lung carcinoma cell line was purchased from Cell Lines Service (CLS, Eppelheim, Germany). ASB-XIV cells were maintained in Dulbecco's modified Eagle's medium with 10% fetal bovine serum (Gibco, Waltham, MA, USA), 100 U/mL penicillin, and 100 μg/mL streptomycin (Gibco) at 37 °C with 5% CO₂. BALB/c mice (7 weeks old, female) were purchased from Orient Bio, Inc. (Seongnam, Republic of Korea). All procedures were performed in accordance with the Guide for the Care and Use of

Multifunctional immunomodulatory effects of NE (R848) in vitro: T cell activations and polarization of immunosuppressive cells into immunostimulatory APCs

The multifunctional immunomodulatory effect of NE (R848)-based cancer vaccines stimulates immune responses and ameliorates immune suppression of the TME. NE denotes a squalene-based oil-in-water emulsion comprising 5% Span 85 and 5% Tween 80 surfactants to stabilize its structure. Briefly, NE (R848) was synthesized by dispersing R848 in squalene NE using oleic acid (CH₃(CH₂)₇CH=CH(CH₂)₇COOH), a fatty acid classified as monounsaturated omega 9 and a weak acid.²⁸ As R848 is a weak base because of

Discussion

In this study, we demonstrated both local and systemic antitumor effects of the NE (R848)-adjuvanted cancer vaccine alone and in combination with anti-PD-1 in subcutaneous and orthotopic mouse lung cancer models. Furthermore, we revealed the underlying mechanisms of antitumor activity of a cancer vaccine adjuvanted with NE (R848), which reprograms the TME by converting MDSCs into mature myeloid cells and M2 macrophages into M1 macrophages. These findings were confirmed by the finding that the

CRediT Author Statement

Conceptualization and research design: YTL, M-JA, JK, SK, and S-YK; Conducting experiments: JK, SK, SNL, S-YK, J-EK, KYL, MSK, YMP, and JYH; Data acquisition: JK, SK, SNL, and KL; Data analysis: JK, SK, SNL, KYL, and BMK; Writing the manuscript: JK and SK; Providing expertise and feedback: J-MS, S-HL, JSA, KP, SY, and S-JH; Supervision and final manuscript confirmation: YTL and M-JA. All authors read and approved the final manuscript.

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (Grant Nos. 2017R1A5A1014560, 2018M3A9H4078701, 2020R1A2C3006888, 2017M3C9A6044633, and 2017H1A2A1044327).

Conflicts of interests

None declared.

¹: These authors equally contributed to this work.

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Original ArticleTherapeutic efficacy of cancer vaccine adjuvanted with nanoemulsion loaded with TLR7/8 agonist in lung cancer model

Abstract

Graphical Abstract

Section snippets

Cell culture and animals

Multifunctional immunomodulatory effects of NE (R848) in vitro: T cell activations and polarization of immunosuppressive cells into immunostimulatory APCs

Discussion

CRediT Author Statement

Semin Oncol

Trends Immunol

Comput Struct Biotechnol J

Lancet

Semin Immunol

Immunity

Biomaterials

Trends Mol Med

Semin Immunol

Therapeutic cancer vaccines

J Clin Invest

Immunotherapy of cancer in 2012

CA Cancer J Clin

Cancer immunotherapy for metastasis: past, present and future

Brief Funct Genomics

Understanding the tumor immune microenvironment (TIME) for effective therapy

Nat Med

Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target?

Cancer Sci

How regulatory T cells work

Nat Rev Immunol

T-regulatory cells: key players in tumor immune escape and angiogenesis

Cancer Res

Regulatory T cells in tumor microenvironment and approach for anticancer immunotherapy

Immune Netw

Myeloid-derived suppressor cells as regulators of the immune system

Nat Rev Immunol

Myeloid-derived suppressor cells in hematologic diseases

HemaSphere

The engagement between MDSCs and metastases: partners in crime

Front Oncol

Original Article
Therapeutic efficacy of cancer vaccine adjuvanted with nanoemulsion loaded with TLR7/8 agonist in lung cancer model