Role of Trem1 in ultraviolet radiation-induced immune suppression

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Ultraviolet B (UVB) radiation (290-320 nm) causes immune suppression, in addition to inducing mutant cells. Tumors will occur only when there are mutant cells in an immune suppressive environment. Organ transplant recipients who are treated with immunosuppressive medications have a greatly increased risk (up to 100 times) of UV induced skin cancers and the tumors that do develop behave more aggressively. In the United States, the incidence of skin cancer has doubled from 1992 to 2012. Over 3.5 million new cases are diagnosed each year. The epidemic of skin cancer represents a major public health issue and is a tremendous cost to healthcare systems in the United States and worldwide. It is highly desired to understand the pathogenesis of UVB induced immune suppression and develop new strategies for prevention and treatment. Our preliminary data show that UVB increases Triggering receptor expressed on myeloid cells (Trem)-1 in mouse and human skin tissues and by a portion of CD11b+ cells from the mouse skin and draining lymph nodes. Importantly, we have, for the first time demonstrated that blocking Trem1 with an antagonist peptide inhibits UVB induced immune suppression. Moreover, blocking Trem1 inhibits UVB induced cutaneous carcinogenesis. The findings reveal a previously unrecognized role of Trem1 in UVB induced immune suppression and skin carcinogenesis. Furthermore, a common concept is that UVB induced tolerogenic antigen presenting cells (APC) are required for the induction of immune suppression. Although strong evidence in human and animal studies indicates that CD11b+ cells contain tolerogenic APC, CD11b+ cells are heterogeneous and specific tolerogenic APC remain to be identified. Our data show that UVB induces Trem1 expression by a novel subset of conventional dendritic cell type 2 (cDC2) cells (CD11b+). The UVB induced Trem1+ cDC2 cells in the draining lymph nodes express high levels of immune inhibitory molecules CD200 and PD-L1 and are hardly detectable in normal mice. These findings define novel Trem1+ cDC2 cells and implicate novel mechanisms for Trem1 mediated immune suppression. It forms a strong premise for our hypothesis that UVB induced Trem1+ cDC2 are tolerogenic APC responsible for UVB induced immune suppression and skin carcinogenesis. Targeting Trem1+ cDC2 cells has translational potentials for the prevention and treatment of UVB induced carcinogenesis. Based on the novel findings, proposed studies will examine the hypothesis in animals and humans. Aim 1 will identify UVB induced Trem1+ cDC2 cells as specific tolerogenic APC and determine mechanisms for their immune suppressive activity. Aim 2 will determine mechanisms for the development of UVB induced Trem1+ cDC2 cells. Aim 3 will determine UVB induced Trem1+ cDC2 cells in human skin and blood and determine their roles in immune suppression. Collectively, the current application will apply advanced technology and use genetic and pharmacological approaches to fully characterize the Trem1+ cDC2 cells and explore new mechanisms for UVB induced immune suppression. The outcome will have impacts in the research field and may be exploited to new strategies for prevention and treatment of skin cancers.