Oncotarget

Research Papers:

Lymphatic dysfunction attenuates tumor immunity through impaired antigen presentation

Takayuki Kimura _, Makoto Sugaya, Tomonori Oka, Andrew Blauvelt, Hitoshi Okochi and Shinichi Sato

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Oncotarget. 2015; 6:18081-18093. https://doi.org/10.18632/oncotarget.4018

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Abstract

Takayuki Kimura1,2, Makoto Sugaya1,2, Tomonori Oka1,2, Andrew Blauvelt3, Hitoshi Okochi2, Shinichi Sato1

1Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan

2Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

3Oregon Medical Research Center, Portland, Oregan, USA

Correspondence to:

Makoto Sugaya, e-mail: sugayam-der@h.u-tokyo.ac.jp

Keywords: lymphatics, lymphedema, tumor immunity, cytotoxic T cells

Received: March 18, 2015     Accepted: May 11, 2015     Published: May 27, 2015

ABSTRACT

Tumor growth and metastasis of cancer involve autonomous tumor cell growth and host-tumor interactions. While tumor-specific immunity has been intensively studied in vitro, dynamic roles of lymphatic transport on tumor immunity in vivo have not been fully elucidated. In this study, we examined tumor growth and anti-tumor immune responses using kCYC mice, which demonstrate severe lymphatic dysfunction. Primary tumor growth was augmented in kCYC mice (compared to wild-type mice) when B16 melanoma or EL-4 lymphoma cells were subcutaneously injected. Expression of inflammatory cytokines such as IFN-γ, TNF-α, and IL-2 as well as IL-10 expression in draining lymph nodes (LNs) was significantly reduced in kCYC mice after tumor inoculation. Moreover, decreased levels of tumor-associated antigens were detected in draining LNs in kCYC mice, together with impaired antigen presentation. CD8+ T cells in draining LNs derived from kCYC mice bearing B16 melanoma also showed significantly decreased cytotoxic activity in vitro. Finally, tumor suppression activity of CD8+ T cells derived from kCYC mice bearing B16 melanoma was reduced when adoptively transferred to naive wild-type mice. In summary, these findings suggest that lymphatic transport is essential in generating optimal tumor-specific immune responses mediated by CD8+ T cells.


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