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Chitosan hydrogel containing GMCSF and a cancer drug exerts synergistic anti-tumor effects via the induction of CD8+ T cell-mediated anti-tumor immunity

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Abstract

Cancer treatments consisting of a combination of chemotherapy and immunotherapy have been vigorously exploited to further improve the efficacy of cancer therapies. In this study, we utilized a chitosan hydrogel (CH) system loaded with GMCSF and a cancer drug as a chemo-immunotherapeutic agent in an effort to assess the effects on tumor growth in mice using TC-1 cervical tumor cells, which express the tumor-specific antigen, HPV-16 E7. The growth of TC-1 tumors was significantly reduced in mice treated with a CH harboring a cancer drug (doxorubicin (DOX), cisplatin (CDDP), or cyclophosphamide (CTX)) and GMCSF (CH-a cancer drug + GMCSF), as compared to other groups that were treated with CH containing only a cancer drug(CH-a cancer drug) or GMCSF(CH-GMCSF). Among the cancer drugs, CTX exerted the most potent anti-tumor effects. Interestingly, the intra-tumoral injection of CH-a cancer drug + GMCSF induced a significant E7-specific CD8+ T cell immune response as compared to CH-GMCSF or CH-a cancer drug. This enhancement of tumor antigen-specific CD8+ T cell immunity was associated principally with the anti-tumor effects induced by CH-CTX + GMCSF, as demonstrated by antibody depletion. Collectively, the aforementioned results indicate that co-treatment of tumors with a combination of GMCSF and a cancer drug incorporated into a CH system results in synergistic anti-tumor effects, which occur via the induction of a tumor antigen-specific CD8+ T cell-mediated anti-tumor immunity. This study demonstrates the use of a biodegradable hydrogel system for the co-delivery of an immunoadjuvant and an anti-cancer drug for successful chemo-immunotherapy.

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Abbreviations

APC:

Antigen presenting cell

CDDP:

Cisplatin

CH:

Chitosan hydrogel

CTL:

Cytotoxic T lymphocyte

CTX:

Cyclophosphamide

DCs:

Dendritic cells

DOX:

Doxorubicin

EGCG:

Epigallocatechin-3-gallate

HPV 16:

Human papilloma virus 16

IFN-γ:

Interferon-γ

IL:

Interleukin

MHC:

Major histocompatibility complex

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Acknowledgments

This study was supported by a grant from the SRC/ERC program of the KOSEF/MOST (R11-2005-017-03003-0) and a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (070355).

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Authors and Affiliations

  1. Department of Dermatology, Korea University Ansan Hospital, Korea University College of Medicine, Gojan 1-dong, Danwon-gu, Ansan-si, Gyeonggi-do, 425-707, South Korea

    Soo Hong Seo & Sang Wook Son

  2. Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Gojan 1-dong Danwon-gu, Ansan-si, Gyeonggi-do, 425-707, South Korea

    Hee Dong Han, Kyung Hee Noh & Tae Woo Kim

  3. Departments of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Hee Dong Han

  4. Research Center for Women’s Diseases, Sookmyung Women’s University, Seoul, 140-742, South Korea

    Tae Woo Kim

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  1. Soo Hong Seo
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  2. Hee Dong Han
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  3. Kyung Hee Noh
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  4. Tae Woo Kim
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Correspondence to Tae Woo Kim or Sang Wook Son.

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Soo Hong Seo and Hee Dong Han contributed equally to this paper.

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Seo, S.H., Han, H.D., Noh, K.H. et al. Chitosan hydrogel containing GMCSF and a cancer drug exerts synergistic anti-tumor effects via the induction of CD8+ T cell-mediated anti-tumor immunity. Clin Exp Metastasis 26, 179–187 (2009). https://doi.org/10.1007/s10585-008-9228-5

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