PROJECT SUMMARY
Breast cancer is estimated to be the most diagnosed cancer in American women and account for 15% of female
cancer-related deaths in 2023. Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective
and durable treatment strategies due to the absence of targetable cell surface receptors, including ER, PR, and
HER2. Consequently, TNBC patients face the worst prognosis among breast cancer subtypes. Adaptive immune
activity in the tumor microenvironment is a well-known prognostic indicator within TNBC patients and is correlated
with treatment benefit. However, tumors frequently evolve to avoid immune recognition, which negatively impacts
patient prognosis. Clinical data from paired primary and metastatic breast tumors demonstrate that TNBC
metastases commonly downregulate expression of genes involved in major histocompatibility complex Class I
(MHC-I) antigen presentation, a mechanism by which CD8+ cytotoxic T cells can recognize and kill tumor cells
displaying aberrant neoantigens. Therefore, understanding and addressing tumor immune evasion mediated by
loss of MHC-I has the potential to improve TNBC patient outcomes. Our central hypothesis is that breast tumor
MHC-I loss results in a unique immune-evasive phenotype that can be overcome through novel treatment
modalities.
This proposed research will functionally and molecularly characterize MHC-I-low breast tumors and evaluate
customized combination immunotherapy approaches to enhance anti-tumor adaptive immunity. Experiments in
Aim 1 will determine how MHC-I loss affects tumor progression and immune cell infiltration, through both in vivo
immunocompetent mouse models and computational analysis of human clinical breast cancer datasets. In Aim
2, I will assess whether a CD40 agonist or demethylating agent will increase the efficacy of immunotherapy
against MHC-I-low tumors. Altogether, this work will comprehensively inform how MHC-I-mediated immune
evasion affects multiple facets of breast tumor biology and which therapeutic strategies should be explored in
the clinic to improve patient outcomes.