Lymphatic dysfunction attenuates tumor immunity through impaired antigen presentation

// Takayuki Kimura 1, 2 , Makoto Sugaya 1, 2 , Tomonori Oka 1, 2 , Andrew Blauvelt 3 , Hitoshi Okochi 2 , Shinichi Sato 1 1 Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan 2 Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan 3 Oregon 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.