UC San Diego

Following initial therapy responses, tumors often relapse leading to patient mortality. How cancer cells change from a therapy sensitive to a therapy resistant state is poorly understood, particularly in the context of cytotoxic CD8 T cells mediated immunotherapy. Multiple studies have identified mechanisms by which residual tumor cells avoid CD8 T cell activation, but thus far there have been no studies focused on whether residual tumor cells survive continuous exposure to and attack by activated CD8 T cells. We hypothesized that in addition to commonly proposed evasive mechanisms, cancer cells can enter an immunotherapy-tolerant persister cell state to survive activated CD8 T cell attack. Here, we report the observation of a subpopulation of quiescent immunotherapy persister cells which survive through a reversible, non-genetic mechanism. Upon extended cytotoxic T cell pressure, a subset of immunotherapy persister cells reenter the cell cycle and regrow into overtly resistant colonies which may represent the initial events of acquired resistance and tumor recurrence. These findings suggest that cancer cells may survive initial T cell cytotoxicity exposure through a quiescent persister state for several weeks prior to relapse. Interestingly, we found that immunotherapy persister cells survive despite continual T cell activation and experience sublethal activation of apoptotic signaling. Together, these studies reveal a novel population of tumor cells which survive extended CD8 T cell attack and may seed tumor recurrence during acquired resistance to immunotherapy.