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A combination of immunoadjuvant nanocomplexes and dendritic cell vaccines in the presence of immune checkpoint blockade for effective cancer immunotherapy

Cellular & Molecular Immunology volume 18, pages 1599–1601 (2021)Cite this article

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Nanovaccines are used as delivery platforms for antigens and adjuvants, which activate antigen-presenting cells (APCs) and enhance anticancer immune responses.1,2 Researchers have recently developed a self-assembled nanocomplex using a polysorbitol-co-PEI (PSPEI) polymer complexed with poly(I:C) (PIC). By binding to different surface proteins, this nanocomplex enhances the intracellular delivery of cargos and induces potent anticancer immune responses against melanoma cells.3 We have previously demonstrated that PD-1/PD-L1 blockade enhanced the efficacy of DC-based cancer immunotherapy.4,5 Moreover, the combination of nanomedicines and PD-L1 blockade has been reported to enhance CD8+ T cell activation and inhibit immunosuppressive cells within the tumor microenvironment.6 In the present study, we investigated the therapeutic efficacy of a combinatorial treatment comprising the immunoadjuvant nanocomplex PSPEI-PIC, a DC vaccine, and PD-L1 blockade in a murine colon cancer model.

We found that ~97% of MC-38 cells and ~6% of BM-derived DCs expressed PD-L1 (Fig. S2C, D). To gain further insight into the immunological mechanisms underlying the potent antitumor effects of PSPEI-PIC + DCs + PD-L1 blockade, we evaluated the effects of the combination therapy on the immune response on days 22, 26, and 29 post treatment. Mice treated with PSPEI-PIC alone, DCs alone, and PSPEI-PIC + DCs expressed higher levels of PD-L1 in the spleens and tumors than mice treated with anti-PD-L1 alone or the PBS control. By contrast, the spleens and tumors of mice treated with PSPEI-PIC + PD-L1 blockade and PSPEI-PIC + DCs + PD-L1 blockade exhibited the lowest percentage of PD-L1-expressing cells among all groups (Fig. S4A–F). In addition, restimulated splenocytes and serum from mice treated with PSPEI-PIC + DCs + PD-L1 blockade increased IFN-γ levels and decreased IL-10 and TGF-β levels (Fig. S5A–E). Importantly, mice in the PSPEI-PIC + DCs + PD-L1 blockade group exhibited the highest proportions of splenic M1 macrophages (Fig. S6A, B), CD4+CD44+ T cells (Fig. S7A, B), CD8+CD44+ T cells (Fig. S7C, D), effector NK cells (Fig. S8A, B), CD4+ TEM cells (Fig. S9A, B), and CD8+ TEM cells (Fig. S9C, D) among all groups. Moreover, mice in the PSPEI-PIC + DCs + PD-L1 blockade group displayed a trend toward higher proportions of tumor-infiltrating CD8+CD69+ T cells (Fig. S10A–D), CD8+CD44+ T cells (Fig. S10E–H), CD8+ TCM cells (Fig. S9E–H), CD4+CD44+ T cells (Fig. S7E–H), effector NK cells (Fig. S8C–F), and M1 macrophages (Fig. S6D, E, G, H) among all treatment groups, in both the injected and distant tumors. Interestingly, treatment with PSPEI-PIC + DCs + PD-L1 blockade promoted the activation of CD62L(lo)CD44(hi) splenic effector cells (Fig. S9A–D), which is necessary for their efficient activation and migration to injected and distant tumors. Upon migration into the tumor microenvironment, effector cells become CD62L(hi)CD44(hi) (Fig. S9E–H), allowing them to reside in the tumor microenvironment to kill cancer cells. In addition, mice treated with PSPEI-PIC + DCs + PD-L1 blockade showed a trend toward lower percentages of M2 macrophages (Fig. S6A, C, D, F; Fig. 6G, I), Tregs (Fig. S11A–F), and MDSCs (Fig. S12A–S12) in the spleen and in both the injected and distant tumors. Furthermore, mice treated with PSPEI-PIC + DCs + PD-L1 blockade produced the lowest levels of IL-10 (Fig. S13A), VEGF (Fig. S13B), and TGF-β (Fig. S13C) among all groups. These results indicate that the combination of PSPEI-PIC, DCs, and PD-L1 blockade promotes the infiltration of effector immune cells, inhibits immunosuppressive cells and strongly suppresses the production of angiogenic factors (VEGF) and inhibitory cytokines (TGF-β and IL-10) in the spleen and tumor microenvironment of treated mice, which showed a clear correlation with tumor suppression at both injected and distant sites.

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Acknowledgements

This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2018R1A5A2024181, 2020R1A2C2010098).

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  1. These authors contributed equally: Manh-Cuong Vo, Seo-Yeon Ahn, Tan-Huy Chu

Authors and Affiliations

  1. Institute of Research and Development, Duy Tan University, Danang, Vietnam

    Manh-Cuong Vo

  2. Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea

    Manh-Cuong Vo, Seo-Yeon Ahn, Tan-Huy Chu, Thangaraj Jaya Lakshmi, Sung-Hoon Jung & Je-Jung Lee

  3. Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea

    Manh-Cuong Vo, Seo-Yeon Ahn, Mihee Kim, Ga-Young Song, Sung-Hoon Jung, Deok-Hwan Yang, Jae-Sook Ahn, Hyeoung-Joon Kim & Je-Jung Lee

  4. Department of Polymer Science and Engineering, Chungnam National University, Daejeon, Republic of Korea

    Saji Uthaman

  5. Department of Biomedical Science, Chonnam National University Medical School, Gwangju, Republic of Korea

    Shammer Pillarisetti & In-Kyu Park

  6. Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, South Korea

    Tung Nguyen Thanh Uong

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Correspondence to In-Kyu Park or Je-Jung Lee.

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Vo, MC., Ahn, SY., Chu, TH. et al. A combination of immunoadjuvant nanocomplexes and dendritic cell vaccines in the presence of immune checkpoint blockade for effective cancer immunotherapy. Cell Mol Immunol 18, 1599–1601 (2021). https://doi.org/10.1038/s41423-021-00666-z

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