SUMMARY Therapeutic blocking of the PD1 pathway results in significant tumor responses but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways, and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.

Summary MCL1, which encodes the anti-apoptotic protein MCL1, is among the most frequently amplified genes in human cancer. A chemical genomic screen identified compounds, including anthracyclines, that decreased MCL1 expression. Genomic profiling indicated that those compounds were global transcriptional repressors that preferentially affect MCL1 due to its short mRNA half-life. Transcriptional repressors and MCL1 shRNAs induced apoptosis in the same cancer cell lines and could be rescued by physiological levels of ectopic MCL1 expression. Repression of MCL1 released the pro-apoptotic protein BAK from MCL1, and Bak deficiency conferred resistance to transcriptional repressors. A computational model, validated in vivo, indicated that high BCL-xL expression confers resistance to MCL1 repression, thereby identifying a patient selection strategy for the clinical development of MCL1 inhibitors.