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Significance Immune checkpoint blockade (ICB) has revolutionized treatment of many cancer types, but the majority of treated patients still do not respond to ICB. There is an urgent need to identify predictive biomarkers of response prior to or shortly after therapy initiation, as well as the underlying mechanisms. Here we utilize a model of bilateral tumor implantations followed by resection and immunotherapy-response assessment to study the tumor microenvironment shortly following treatment, identifying biomarkers for response or resistance at early time points. Our biomarker gene signatures derived from CD8+ T cells significantly segregate patients by survival and associate with patient response to ICB. Our findings provide a general approach for studying mechanisms of resistance to ICB and discovering predictive biomarkers of response.

A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade