Determinants of Response and Resistance to DNA-Damaging Radiation Plus Immunotherapy Combinations in Triple Negative Breast Cancer
UNC Breast SPORE Research Project 2
Combining immune checkpoint inhibition with chemotherapy has transformed outcomes for patients with early stage triple negative breast cancer (TNBC).
However, treatment resistance and treatment-related toxicities persist as dual challenges that must be overcome with new strategies to guide personalized chemo-immunotherapy combinations.
We are investigating the role of DNA damage-induced necroptosis (inflammatory cell death) as a determinant of response to radiation therapy plus anti-PD1 (aPD1) immune checkpoint inhibitor combination therapy.
We use TNBC genetically engineered mouse models and correlative biomarker analyses of pre/post-treatment primary tumor, metastatic lymph node, and blood specimens from an ongoing clinical trial of preoperative aPD1 therapy, with or without radiation therapy, in early-stage TNBC with lymph node metastasis.

Project Aims
Aim 1
Assess necroptosis as a predictive biomarker of response to radiation therapy/aPD1 combination therapy in triple negative breast cancer.
Aim 2
Evaluate therapeutic neoantigen vaccination as a strategy to overcome ion therapy/aPD1 resistance induced by necroptosis deficiency.