Project Summary/Abstract:
The incidence rate of cutaneous melanoma has doubled since 1973, and is increasing more rapidly than any
other cancer. FDA-approved targeted inhibitors and immune checkpoint therapies have high response rates in
melanoma; however, both innate and acquired resistance remain significant issues. Strategies that combine
targeted and immune therapy show promise; however, a comprehensive understanding of the crosstalk
between cancer cells and immune cells is lacking. Our central hypothesis is that tumor intrinsic signaling
modulates the anti-tumor immune response, and elucidation of pathways that drive these interactions can lead
to novel therapeutic strategies. Through the successful completion of the following two aims, we will gain
insight into tumor intrinsic signaling pathways that regulate anti-tumor immunity. In the F99 phase, we are
investigating a novel regulation of the understudied immune checkpoint protein VISTA. VISTA is an inhibitory
immune checkpoint primarily expressed on hematopoietic cells. In a novel finding, we observed that VISTA is
expressed on melanoma cells in patient samples and in cell lines. Its tumor-specific expression promoted
tumor initiation in vivo, associated with an increase in Foxp3+ CD4+ T regulatory cells (Tregs). We
demonstrated that BRAF inhibitor (BRAFi) treatment reduced VISTA expression, and BRAFi-induced
upregulation of FOXD3 negatively regulated VISTA transcript levels. BRAF/MEK inhibitors are used clinically,
which motivates us to further investigate the role of VISTA, a BRAF-FOXD3-regulated immune checkpoint
protein, in modulating immune responses. In the first aim, we will test the hypothesis that tumor-expressed
VISTA promotes Treg induction and enhances Treg suppressive function. Tregs can limit the efficacy of
immunotherapy; thus, we will also test the hypothesis that tumor-specific expression of VISTA alters the
response to PD-1 blockade. In the K00 phase, we will broadly investigate cancer cell signaling pathways that
allow cells to evade immune detection during metastasis. Tumor cells employ various mechanisms to depart
from the primary tumor site and colonize new organs. We hypothesize that tumor intrinsic signaling pathways
play a critical role in immune evasion during metastasis. In aim 2, we will use a CRISPR/Cas9 screen in a
spontaneous metastasis model to identify genes that promote metastasis. We will compare results between
immune competent and immune compromised models to determine genes that specifically promote metastasis
when under pressure from the immune system. Completion of these studies will bring valuable insights into the
complex interactions between tumor and immune cells. The training provided in both of these phases will build
a solid foundation in cancer biology, tumor immunology, and metastasis, contributing towards the long-term
goal of conducting research on tumor immunology as an academic principal investigator.