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

Abstract

Persisters are a rare sub-population of tumor cells that survive anti-cancer therapy and are thought to be a major cause of recurrence. These cells have been identified following both drug- and immune-therapy but are generally considered to be distinct entities. Since both pharmacological agents and immune cells often kill via apoptosis, we tested a hypothesis that both types of cells survive based on reduced mitochondrial apoptotic sensitivity, which in turn would yield a similar and reciprocal multi-agent resistant phenotype. Supporting this hypothesis, we indeed observed that IPCs acquired a reduced sensitivity to multiple drug classes and radiotherapy, suggesting non-immune mechanisms are important in the survival of cancer cells after immunotherapy. Likewise, DTPs developed not only a reduced sensitivity to multiple drug classes and radiotherapy, but also acquired a reduced sensitivity to T cell killing. Both IPCs and DTPs developed a decreased sensitivity to mitochondrial apoptosis. A sub-population of IPCs downregulated antigen and upregulated PD-L1. Intriguingly, in the IPCs that didnt employ these mechanisms of resistance, a greater decrease in sensitivity to mitochondrial apoptosis was observed, suggesting that the presence or absence of a resistance mechanism can exert selective pressures over the emergence of others. Targeting anti-apoptotic dependencies in persisters increased sensitivity to chemotherapy or CAR T therapy. These results suggest that common biological mechanisms underly survival of persisters, whether derived from immune or drug therapy, and offer an explanation for the acquired cross-resistance to these two types of therapies often observed in the clinic. HighlightsO_LIImmunotherapy persister cells (IPCs) are less sensitive to drugs and radiation. C_LIO_LIDrug tolerant persisters (DTPs) are less sensitive to radiation and CAR T cell attack. C_LIO_LIIPCs and DTPs are less sensitive to mitochondrial apoptosis. C_LIO_LITargeting anti-apoptotic dependencies helps eliminate IPCs/DTPs. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/641492v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@fe98b4org.highwire.dtl.DTLVardef@db7bfdorg.highwire.dtl.DTLVardef@1a94469org.highwire.dtl.DTLVardef@1ca6b2c_HPS_FORMAT_FIGEXP M_FIG C_FIG