Prioritization of prostate cancer to immune checkpoint therapy by ranking tumors along IFN-γ axis and identification of immune resistance mechanisms

Abstract

We propose priotirization of prostate cancer patients to PD-L1 checkpoint therapy by assessing activity of IFN-{gamma}/PD-L1 signaling in tumor from transcriptional profile. To this end, we introduced a new approach for inferring pathway activity and suppression (IPAS) by assessing significance of positioning pathways genes expression levels at top (activation) or bottom (suppression) in gene expression profile of a given tumor. By ordering tumors along IFN-{gamma}/PD-L1 axis, we determined distinct "IFN-{gamma}-depleted" and "IFN-{gamma}-enriched" immune subtypes, genes involved in immune evasion and potential targets for combination therapy. Using IPAS scoring method, we proposed biomarker panels for accurate ranking tumors along IFN-{gamma}/PD-L1 axis.