Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline loss-of-function
mutations in the TSC1 or TSC2 gene. Renal disease, which includes angiomyolipomas, cysts, and carcinomas,
is the second leading cause of morbidity and mortality in TSC.
In unpublished data, we found increased immunosuppressive CD206-positive macrophages and high expression
of the immune checkpoint molecule B7-H3 (a homolog of PD-L1) in human TSC renal cysts and
angiomyolipomas. We also demonstrate that B7-H3 promotes TSC2-null cell growth in vivo via a mechanism
that requires CD8+ T cells.
These and other data lead to our central hypothesis: immunosuppressive macrophages together with B7-H3
expression on TSC2-deficient cells promote renal disease in TSC. A key translational corollary of this
hypothesis is that immunosuppressive macrophages and B7-H3 are potential therapeutic targets for TSC.
Aim 1: To identify the mechanisms through which macrophages contribute to the renal manifestations
of TSC. We will test the hypothesis that immunosuppressive macrophages promote TSC1- and TSC2-deficient
cell growth directly, and/or indirectly via inhibition of CD8+ T cell function.
Aim 2: To determine how B7-H3 remodels the immune microenvironment of TSC-associated renal
disease. We will test the hypothesis that B7-H3 promotes TSC2-null cell growth by inhibiting CD8+ T cell function.
Aim 3: To investigate the preclinical efficacy of co-targeting macrophages and B7-H3 in TSC. We will test
the hypothesis that targeting both immunosuppressive macrophages and B7-H3 will lead to long-lasting, durable
responses in preclinical models of renal disease driven by loss of Tsc1 or Tsc2.
We expect this project to have scientific impact by identifying the immune mechanisms responsible for the
growth of TSC2-null cells in the kidney. These mechanisms may have broad implications, since macrophages
are believed to play a key role in other renal diseases, including autosomal dominant polycystic kidney disease
(ADPKD). Our areas of innovation include our novel, translationally relevant hypotheses as well as technical
innovation, including CITE-seq, spatial CODEX and nanoString transcriptomic profiling, and a novel, unpublished
mouse model of renal disease in TSC (Rosa26-CreERT2 Tsc2f/f).
