TIM-4 glycoprotein-mediated degradation of dying tumor cells by

 autophagy leads to reduced antigen presentation and increased

 immune tolerance

Baghdadi M1, Yoneda A1, Yamashina T1, Nagao H1, Komohara Y2, Nagai S3, Akiba H4, Foretz M5, Yoshiyama H1, Kinoshita I6, Dosaka-Akita H6, Takeya M2,Viollet B5, Yagita H4, Jinushi M7. Immunity, 2013 Dec 12; 39(6):1070-81

Speaker: Dong-Jer Shiau (蕭東哲)            Time: 15:10~16:00, May 28, 2014

Commentator:Dr. Jiu-Yao Wang (王志堯老師)  Place: Room 5761

Abstract:

Tumor cells avoid to be cleaned by host immune cells, establishing many pathways to evade immune response. Previous studied show that tumor microenvironment contenting immune cellsinfiltration mediate tumor progression, drug resistance (1) and repression antitumor ability of immune cell to maintain tumor survival. Moreover T cell immunoglobulin and mucin domain protein-4(TIM4), which is expression on myeloid cells regulates T cell homeostasis. In addition, TIM-4 play a role in phagocytosis of apoptotic cell by APCs through interaction withphosphatidylserine(PS) (2). In this study, authors want to know whether TIM-4 play a role in tumor microenvironment. In result, TIM-4 is up-regulated expression in tumor associated macrophages, which culture with DAMPs from dying tumor cell treated tumor drug. However, TIM-4 does not play a majored role in regulating TAMs phagocytosis compare wild type with TIM-4^-/- TAMs. In addition, TIM-4 promoted autophagy formation by activating AMPK, and over-degradation engulfed dying tumor cell. Therefore, APC which expression TIM-4 engulfed dying tumor cell cannot present tumor antigen to prime CD 8⁺ T cells. So TIM-4 mediating autophagy over-degradation dying tumor cell, promoting tumor cell tolerance. TIM-4 play a role to suppression immune response for tumor cell survival. Therefore, TIM-4 is a new drug target to treatment cancer.

References:

1.       Hanahan D et al., Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012 Mar 20;21(3):309-22.

2.    Kobayashi N et al., TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells Immunity. 2007 Dec;27(6):927-40.