Programmed cell death/apoptosis occurs throughout life in all tissues of the body and more than a billion of cells die everyday as part of normal processes. Thus rapid and efficient clearance of cell corpses is a vital prerequisite for homeostatic maintenance of tissue health. Failure to clear dying cells can lead to the accumulation of autoantigens in tissues that foster diseases such as cancer, chronic inflammation, autoimmunity and developmental abnormalities. High level of cell death can occur within tumor environment in cancer therapy, and the mechanisms through which dying tumor cells are cleared influence tumor-specific immunity. Thus, manipulation of the immunological context of dead cell removal has great potential for the control of tumor progression and generation of an antitumor response, which is still an outstanding issue and understanding this specific mechanism warrants investigation. Enormous efforts have been made toward understanding various mechanisms of tumor suppressor p53-mediated cell death/apoptosis. However, the involvement of p53 in post- apoptosis has not been implicated until now. In this application, we identified a first post- apoptotic target gene of p53, death domain1?, DD1?, which is highly responsive to genotoxic stresses/DNA damage. We found that p53 controls apoptotic cell clearance of through its target DD1?, suggesting that p53 promotes both the pro-apoptotic pathway and the post-apoptotic events. Moreover, DD1? appears to function as a negative immune-checkpoint regulator that modulates immune responses/T cell function, suggesting the role of DD1? in immune tolerance. DD1? has similarity with several members of the immunoglobulin superfamily with the IgV domain, including TIM family proteins and immune checkpoint co-inhibitors PD-1 and PD-L1. The public database indicates that expression of DD1? is increased in multiple human cancers, implicating its immune modulating function in cancer. Based on these data, we propose two major aims focused on mechanisms of understanding the roles of a newly found post-apoptotic target of p53 and investigating the potential to enhance the anti-tumor immune responses.

Public Health Relevance

p53-induced expression of DD1? is a vital phase for the phagocytic engulfment process of dead cells, and then facilitates the step-wise priming of immune surveillance. As a downstream target of the tumor suppressor p53, DD1? activation may extend the repertoire of p53 activities to ?guardian of the immune integrity.?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA203552-01A1
Application #
9194665
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Mccarthy, Susan A
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$368,043
Indirect Cost
$139,293
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114