Generation and analysis of immunity inside tumor tissues

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DESCRIPTION (provided by applicant): Dr. Yu's long term goal is to understand how the immune system responds to syngeneic cancerous cells and tissues, and how stronger immune responses can be promoted against the malignancies. The current application is intended to uncover the mechanisms of how LIGHT, a newly-identified tumor necrosis factor superfamily (TNFSF) member, induces a strong anti-tumor immunity and test the application of LIGHT to tumor immunotherapy in a clinically relevant setting. We know that LIGHT can induce an immune-mediated tumor rejection, however, the mechanisms of how LIGHT provokes such a strong anti-tumor immunity has not been well studied. We strongly believe that LIGHT is a good candidate for tumor immunotherapy in spontaneous metastatic disease, but its full potential has yet to be determined. Our preliminary data suggests that LIGHT can not only attract and stimulate tumor-specific CD8+ T cells, but also regulate NK and CD4+ regulatory T cells. Moreover, our pilot study demonstrates that the utilization of an adeno-LIGHT vector can indeed treat spontaneous metastases in a mouse model. We propose that LIGHT, unlike many other co-stimulatory molecules, has the advantage to regulate both the stromal and hematopoietic immune pathways via its receptors, LT? receptor (LT?R) and Herpes Virus Entry Mediator (HVEM). Specifically, these goals will be pursued with the following three specific aims: Aim 1: To investigate how LIGHT-mediated tumor environment promotes NK function in eliciting tumor rejection and define the roles of NK cells in anti-tumor immunity. Aim 2: Define the role of LIGHT in regulation of CD4+ suppressive T cells inside the tumor. Aim 3: Define the role of LIGHT in promoting immune recognition in spontaneous metastatic tumor models. The expected results from this research will define the mechanisms by which LIGHT mediates anti-tumor immunity and determine ways of delivering LIGHT into the tumor tissue that would be clinically relevant. This study will also elucidate if LIGHT can be utilized as a potential therapeutic agent for treating metastatic disease. Lay language: Despite evidence of tumor antigens that can be recognized by immune system, spontaneous regression of cancers rarely occurs. A molecule LIGHT, expressed on tumors, can induce a rapid tumor regression. This application intends to explore the mechanisms involved as well as develop clinically relevant cancer therapy with LIGHT.