Inhibition of SIRP? in dendritic cells potentiates potent antitumor immunity.

ABSTRACT: Despite their central function in tumor immunity, dendritic cells (DCs) can respond to inhibitory signals and become tolerogenic, curtailing T cell responses in vivo. Here, we provide the evidence for an inhibitory function of signal regulatory protein (SIRP) ? in DC survival and activation. In tumors from human liver cancer patients, infiltrative DCs expressed elevated levels of SIRP?, which is correlated with the induction of immune tolerance within the tumors. Silencing of SIRP? resulted in a significant increase in the longevity of antigen-pulsed DCs in the draining lymph nodes. In addition, SIRP? controls the activation and output of DCs. Silencing of DC-expressed SIRP? induced spontaneous and enhanced production of IL12 and costimulatory molecules, resulting in more potent cytotoxic T lymphocyte responses, including the eradication of previously established solid tumors. SIRP? exerted such effects, at least in part, via the association and sequestration of p85 subunit of PI3K. Thus, SIRP? is a critical regulator of DC lifespan and activity, and its inhibition might improve the clinical efficacy of DC-based tumor vaccines.

SUBMITTER: Liu Q 

PROVIDER: S-EPMC5048764 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature