• Open Access

The critical role of type-1 innate and acquired immunity in tumor immunotherapy

Authors

  • Hiroaki Ikeda,

    1. Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-0815
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  • Kenji Chamoto,

    1. Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-0815
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  • Takemasa Tsuji,

    1. Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-0815
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  • Yoshinori Suzuki,

    1. Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-0815
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  • Daiko Wakita,

    1. Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-0815
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  • Tsuguhide Takeshima,

    1. Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-0815
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  • Takashi Nishimura

    Corresponding author
    1. Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, N-15 W-7, Kita-ku, Sapporo 060-0815
      To whom correspondence should be addressed. E-mail: tak24@igm.hokudai.ac.jp.
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To whom correspondence should be addressed. E-mail: tak24@igm.hokudai.ac.jp.

Abstract

The discovery of a large array of tumor antigens has demonstrated that host lymphocytes can indeed recognize and destroy tumor cells as originally proposed in the cancer immunosurveillance hypothesis. Recent reports that led to the cancer immuno-editing concept also strongly support the immunosurveillance hypothesis, and they further indicate that the host immune system plays a critical role not only in promoting host protection against cancer but also in selecting tumors that can better escape from immune attack. Thus, it is now clear that T cells have the ability to recognize and destroy spontaneously arising tumors. However, the generation of antitumor immunity is often difficult in the tumor-bearing host because of various negative regulatory mechanisms. Here, we review our recent work on tumor immunotherapy, which utilizes the activation of type-1 innate and/or acquired immunity as a potent strategy to overcome immunosuppression in the tumor-bearing host. We have established a variety of tumor therapeutic protocols that aim to activate type-1 immunity, such as tumor-vaccine therapy with CpG encapsulated in liposomes, cell therapy using tumor-specific Th1 cells, and gene therapy using gene-engineered Th1 cells. We found that CpG encapsulated in liposomes stimulated IL-12-producing DC and induced IFN-γ-producing NK cells, NKT cells, and tumor-specific CTL. Th1 cell therapy was also shown to be beneficial for acceleration of APC/Th1 cell-cell interaction in the DLN, which was critical for inducing tumor-specific CTL at the tumor site. Therefore, we conclude that the activation of type-1 innate and acquired immunity is crucial for tumor immunotherapy in order to overcome strong immunosuppression in the tumor-bearing host.

Abbreviations:
APC

antigen presenting cells

α-GalCer

α-galactosylceramide

CEA

carcinoembryonic antigen

clgTCR

chimeric immunoglobulin T cell receptor

CpG-ODN

cytosine-phosphorothioate-guanine containing oligodeoxynucleotides

CTL

cytotoxic T cells

DC

dendritic cells

DLN

draining lymph node

IFN

interferon

IL

interleukin

mAb

monoclonal antibody

MCA

methylcholanthrene

Mo

macrophages

NK

natural killer

NKT

natural killer T

OVA

ovalbumin

RAG

recombination-activating gene

scFv

single-chain variable fragments

Tc

cytotoxic T

TCR

T cell receptor

TGF-β

transforming growth factor-β

Th

helper T

TLR

toll-like receptor

Tr1

T regulatory-1

TRA

tumor-rejection antigens

TRAIL

tumor necrosis factor-related apoptosis-inducing ligand

Treg

regulatory T cells

Ancillary