Tumor tissues gradually form immune barriers that trap antigens and prevent adequate antigen presentation in draining lymph node and prevent CTL expanding and attacking tumor. Furthermore, the local tumor environment induces regulatory T cells that suppress incoming CD8+ cells. The expression of a newly identified TNFSF member, LIGHT, within the tumor induced lymphoid-like structures in the cancerous tissue resulting in tumor rejection at local and distal sites. However, the mechanisms of how LIGHT provoke such strong anti-tumor immunity and whether targeting local tumors with LIGHT can be effective for treating spontaneous metastasis have not been well studied. Our preliminary data suggest that LIGHT not only can attract and stimulate tumor-specific CDS* T cells, but also regulate NK and CD4* suppressive cells, which contribute positively and negatively to tumor rejection, respectively. It is hypothesized that locally targeted tumor with LIGHT induces strong anti-tumor immunity inside tumor through multiple regulation pathways affecting NK, CD4+, CD8+, and stromal cells. We plan to investigate whether and how tumor microenvironments induce immune tolerance and develop new immunotherapies for treating metastatic cancer. Our goal is to explore whether tumor suppressive microenvironment can be effectively altered to generate enough CTL to eradicate distal tumor. Specifically, we will elucidate the mechanisms for LIGHT-mediated tumor rejection and key players inside tumor that regulate positively or negatively CTL.
In aim 1, we will develop new approaches to eradicate metastasis by targeting primary tumors with locally delivered LIGHT.
In aim 2, we will investigate how LIGHT activates NK cells for tumor rejection.
In aim 3, we will determine whether LIGHT can reverse regulatory T cell-mediated suppression within the tumor microenvironment. Therefore, this study will further define the molecular mechanisms for tumor-induced immune evasion and the role of LIGHT on key cellular components inside tumor microenvironment for turner rejection. Furthermore, this study will develop clinically relevant approaches to treating an established cancer and metastatic tumors Lay Language: This study will help us to understand how local treatment of tumors can lead to the rejection of distal tumors and develop possible new immunotherapies for cancers, infectious diseases, and autoimmune diseases.
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