Gaorav Gupta, MD, PhD

Understanding the effects of gene mutations on the immune response to breast cancer.

Impact

Breast cancer remains a prevalent health concern, with a critical need to understand how it develops from early, non-invasive stages to aggressive, invasive tumors. Dr. Gupta’s research aims to explore how the immune system interacts with precancerous cells in the breast, focusing on key mechanisms that could help prevent the progression to invasive breast cancer. DNA damage is known to promote cancer by causing mutations, but it can also activate the immune system to suppress cancer development and improve responses to therapy. A major goal of Dr. Gupta’s research is to understand why sometimes these immune responses protect against cancer and other times fail. This study has the potential to inform new strategies for early detection, prevention, and improved treatments for breast cancer patients.

Progress Thus Far

Over the past year, Dr. Gupta and his team made progress in understanding how the immune system and DNA repair pathways shape the earliest steps of breast cancer development. Using a model system that closely mimics human triple-negative breast cancer (TNBC), the team created one of the first detailed maps of immune changes that occur as precancerous lesions evolve into cancer. They found that early lesions are initially controlled by anti-tumor immune cells, but over time the immune cells become suppressed, allowing tumors to escape immune control. The team also discovered that a specialized form of tumor cell death called necroptosis is required for radiation and anti-PD1 immunotherapy to work effectively. Importantly, this process activates not only T cells, but also B cells and antibody-related immune responses that may be critical for anti-tumor immunity.

Dr. Gupta and his team generated one of the world’s largest paired spatial datasets of breast tumors and tumor-draining lymph nodes from patients enrolled in the P-RAD clinical trial. Remarkably, localized radiation to the breast tumor induced strong immune activation within non-irradiated lymph nodes. These immune responses strongly correlated with treatment response months later, suggesting that radiation-immunotherapy combinations may help eliminate micrometastatic disease by reprogramming systemic anti-tumor immunity rather than acting only as a local therapy.

What’s Next

Dr. Gupta and his team will further define how DNA damage-induced immune signaling suppresses breast cancer development and investigate how necroptosis activates B cell anti-tumor immunity during radiation and immunotherapy treatment. They will also complete biomarker analyses from the P-RAD clinical trial to identify predictors and mechanisms of effective anti-tumor immune responses, work that could help determine which patients are most likely to benefit from radiation-immunotherapy combinations.