PROJECT SUMMARY
The loss of the tumor suppressor gene SMARCB1, a core member of the SWItch/sucrose non-fermentable
(SWI/SNF) chromatin remodeling complex, defines a group of malignancies characterized by a particularly
aggressive clinical course and prominent metastatic behavior. Renal medullary carcinoma (RMC) is the most
commonly diagnosed SMARCB1-deficient renal malignancy and predominantly afflicts young individuals of
African descent carrying the sickle cell trait. SMARCB1-deficient renal malignancies are extremely challenging
diseases that fail to respond to standard-of-care therapeutic regimens used for other renal tumors. In our
recent work, we found that SMARCB1-deficient renal malignancies such as RMC are characterized by a highly
inflamed phenotype, yet demonstrate accelerated tumor progression (hyperprogression) in response to standard
immune checkpoint inhibition (ICI). Our preliminary data in prospectively collected tissue specimens and
immunocompetent genetically engineered mouse models (GEMMs) of RMC suggest that this hyperprogression
following ICI is due to the engagement of myeloid-affiliated transcriptional programs in tumor cells. Our
overarching hypothesis is that the hijacking of myeloid-affiliated transcriptional circuits by SMARCB1-deficient
renal malignancies is the major mechanism driving ICI-induced hyperprogression, which can be prevented by
targeting master myeloid regulators such as S100A9 and the CEBPB/p300 complex. In the first aim, we will
perform immunogenomic profiling studies at the single-cell level in our clinical trial tissue specimens and
immunocompetent GEMMs to determine how ICIs, using anti-PD-1 alone or in combination with either anti-
CTLA-4 or anti-LAG-3, modulate the tumor immune microenvironment to drive hyperprogression via the
engagement of myeloid-affiliated transcriptional pathways. In the second aim, we will perform translational
genomic and pharmacologic experiments in our GEMMs of RMC to determine whether targeting S100A9 or the
CEBPB/p300 complex can induce sensitivity to ICIs in SMARCB1-deficient renal malignancies. In the third aim,
we will utilize a first-in-class technology that enables the retrieval of ICI therapy-resistant clones to investigate
clonal dynamics in our GEMMs and determine the role of SMARCB1 loss in the engagement of myeloid-related
transcriptional pathways and subsequent hyperprogression of tumor cells following ICI treatment. This project is
realistic and feasible within the proposed timeline and budget because it utilizes technology, tissue samples,
and models of SMARCB1-deficient renal malignancies already available to the multidisciplinary research team
of experts and a dedicated translational pipeline led by the PI, Dr. Pavlos Msaouel. Our approach can provide
fundamental information about the mechanisms of ICI-induced hyperprogression in SMARCB1-deficient renal
malignancies, which will substantially improve our understanding of how to optimally elicit antitumor immune
responses and thus will open new therapeutic avenues for these and other diseases driven by loss of SMARCB1
or of other subunits of the SWI/SNF chromatin remodeling complex.