한빛사논문
Sun-Young Kim,†,∥ Sohyun Kim,†,∥ Jung-Eun Kim,† Sang Nam Lee,† Il Woo Shin,† Hong Sik Shin,† Seung Mo Jin,† Young-Woock Noh,‡ Young Ju Kang,‡ Young Seob Kim,§ Tae Heung Kang,§ Yeong-Min Park,§ and Yong Taik Lim*,†
† SKKU Advanced Institute of Nanotechnology (SAINT), Department of Nano Engineering, School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
‡ New Drug Development Center, Osong Medical Innovation Foundation, 123 Osongsaengmyeong-ro, Cheongju, Chungcheongbuk-do 28160, Republic of Korea
§ Department of Immunology, School of Medicine, Konkuk University, 268 Chungwondae-ro, Chungju, Chungcheongbuk-do 27478, Republic of Korea
*Corresponding Author : Yong Taik Lim
Author Contributions
∥S.-Y.K. and S.K. contributed equally to this work.
Abstract
The low therapeutic efficacy of current cancer immunotherapy is related to nonimmunogenic and immunosuppressive tumor microenvironments (TMEs). To overcome these limitations, both the immune priming of antitumoral lymphocytes and the reprogramming of immunosuppressive factors in TMEs are essential. Here, we suggest a nanoemulsion (NE)-based immunotherapeutic platform that can not only modulate tumor-induced suppression but also induce an effective cell-mediated immune response for T cell proliferation. Multifunctional NEs can be fabricated by integrating the efficacy of NEs as delivery systems and the multifaceted immunomodulation characteristics (i.e., immunostimulation and reprogramming of immunosuppression) of small molecule-based Toll-like receptor 7/8 agonists. Local in situ vaccination of melanoma and cervical tumor models with tumor antigens (protein and peptide) adjuvanted with NE loaded with TLR7/8 agonists [NE (TLR7/8a)] induced the recruitment and activation of innate immune cells, infiltration of lymphocytes, and polarization of tumor-associated M2 macrophages, which resulted in inhibition of tumor growth and prolonged survival in both primary and rechallenged tumor models. Antibody-depletion experiments also suggested that macrophages, type I IFN (IFN-α and IFN-β), CD8+ T cells, and NK1.1+ cells contributed to the antitumor effect of NE (TLR7/8a). The combination of antitumoral lymphocytes and reprogramming of immunosuppressive TMEs induced by NE (TLR7/8a) treatment evoked a synergistic antitumor immune response with immune checkpoint blockade therapy (anti-PD-1 and anti-PD-L1).
KEYWORDS : cancer immunotherapy, nanoemulsion, Toll-like receptor agonist, adjuvant, immunosuppression, immunostimulation, immune checkpoint inhibitor
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