In this project, we will use an unbiased approach to identify novel tumor-derived danger signals that alert the innate immune system of a developing malignancy. We are particularly interested in identifying molecules that are expressed by tumor cells very early after a transformation event and before a tumor may manifest clinically. We will focus specifically on melanoma since there is very good evidence of early, but highly varied, immune responses in this malignancy. We have devised a novel mouse model system by which we will be able to induce malignant transformation in vivo and track the affected cell from the time the driver mutations are induced, through pre-malignant stages to the point where an invasive malignancy is formed. This system will allow us to profile the changes in gene expression throughout this course. We hypothesize that novel immune modulating genes are expressed during this progression. By profiling these gene changes from initiation of the malignancy through progression to invasive melanoma in the context of an immune competent and immune deficient background, we hypothesize that we will be able to identify tumor-derived immune modulators that may not be apparent in fully established tumors since immune editing during the progression period may extinguish those genes through an intense selection process.
A substantial amount of evidence indicates that tumor-derived signals alert the innate immune system of a malignant transformation event even before a tumor manifests clinically. However, studies of fully established tumors have likely lost the expression of these signals due to intense selection pressure through a process called immunoediting. We will identify these signals in developing melanoma through a novel approach using an inducible melanoma system.