Drug tolerant persisters and immunotherapy persister cells exhibit cross-resistance and share common survival mechanisms

Persisters are a sub-population of tumor cells that survive anti-cancer therapy facilitating recurrence, and have been identified following drug- and immune-therapy but are generally considered as distinct entities. Drugs and immune cells often kill via apoptosis, therefore, we tested a hypothesis that both types of cells survive based on reduced mitochondrial apoptotic sensitivity, which would yield multi-therapy resistance. We observed that IPCs acquired a reduced sensitivity to multiple drugs and radiotherapy. Likewise, DTPs developed a reduced sensitivity to multiple drugs and radiotherapy, including a reduced sensitivity to T cell killing. IPCs and DTPs were less sensitive to mitochondrial apoptosis. Some IPCs downregulated antigen and upregulated PD-L1. In the IPCs that didn’t employ these mechanisms, a greater decrease in sensitivity to apoptosis occurred. Inhibiting anti-apoptotic dependencies in persisters increased sensitivity to chemotherapy or CAR T therapy. These results suggest that common mechanisms underly survival of persisters, offering an explanation for cross-resistance.