Previously Funded Research

Amruta Bhate, PhD

Stanford University

Research Project:

Investigating role of ADAR1 in improving cancer immunotherapy efficacy in lung adenocarcinoma

Summary:

Cancer immunotherapy drugs called checkpoint inhibitors are one of the most promising approaches for lung cancer treatment today. These drugs target proteins like PD-1, PD-L1, and CTLA-4, which put the ‘brakes’ on the immune response by repressing the ability of T-cells to recognize and kill cancer cells. Checkpoint inhibitors act against these proteins and enable the patient T-cells to ‘see’ the tumors and attack them. However, these therapies are truly effective only in a handful of lung cancer patients as tumors can develop resistance. Therefore, new strategies are needed to enhance the effectiveness of these checkpoint inhibitors. One such approach could be to activate innate immunity in the cancer cells that is elicited when immune cells detect certain pathogenic molecules and actively recruit T-cells to the tumor.

In this study, Dr. Bhate is investigating one such strategy which uses double-stranded RNAs (dsRNAs) present in the tumor cells itself to act as triggers to provoke a robust innate immune response in cancer cells. However, an RNA editing enzyme called ADAR1 can alter RNAs, so they become invisible to the immune system. ADAR1 expression is high in lung cancers, possibly muffling innate immune response. To that end, Dr. Bhate will develop mouse models to investigate genetic and biochemical details of whether silencing ADAR1 can unmask dsRNA and ‘prime’ tumor cells for an innate immune response. When used in combination with checkpoint inhibitors, this approach will help enhance the anti-tumor activity of immunotherapy drugs. This work will reveal how the presence of dsRNAs affect tumor microenvironment and immune response, and whether inhibition of ADAR1 is a feasible therapeutic avenue for lung cancer treatment.