A tritherapy combination of a fusion protein vaccine with immune-modulating doses of sequential chemotherapies in an optimized regimen completely eradicates large tumors in mice

Authors

  • Xinxin Song,

    1. Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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  • Wenzhong Guo,

    1. Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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  • Jianfeng Cui,

    1. Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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  • Xinlai Qian,

    1. Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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  • Linan Yi,

    1. Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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  • Mengjiao Chang,

    1. Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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  • Qiliang Cai,

    1. Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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  • Qingzheng Zhao

    Corresponding author
    1. Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China
    • Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, PO Box 2258, Beijing 100021, People's Republic of China

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    • Tel.: +86 10 87788433, Fax: +86 10 87777447


  • All authors have declared there are no financial conflicts of interest in regard to this work

Abstract

Tumor-induced immunosuppression plays a critical role in both impeding tumor-specific immune responses and limiting the effects of cancer immunotherapy. Analyses of regulatory cells recruited during the growth of the E7-expressing tumor, TC-1, revealed a high percentage of regulatory T cells (Tregs) as well as myeloid-derived suppressor cells (MDSCs) in spleens and tumors. In this study, we proposed that treatment with immune-modulating doses of cyclophosphamide (CTX) and all-trans retinoic acid (ATRA) would result in a beneficial tumor microenvironment with the suppression of Tregs and MDSCs and, thus, enhance the effect of a human papillomavirus protein vaccine. Our results showed that CTX preconditioning and persistent ATRA treatment along with the vaccine achieved long-term survival and induced long-term memory responses. However, the effect of the antitumor response sharply declined when the tritherapy was initiated after the optimal therapeutic time. The more intensive regimen could rescue the effect of the tritherapy accompanied by the decreased percentage of Tregs and MDSCs in spleens and tumors. Besides, a favorable host environment was created by the reduced secretion of interleukin-10 and 6 and vascular endothelial growth factor (VEGF) in the tumor niche and decreased the expression of phosphorylation-signal transducer and activator of transcription 3 of TC-1 tumors. Our data shed light on the immune-modulating doses of sequential chemoimmunotherapeutic strategy targeting not only the tumor but also its microenvironment, which suggests a potential clinical benefit for the immunotherapy of HPV-associated malignancies.

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