T cell subtype profiling measures exhaustion and predicts anti-PD-1 response

Anti-PD-1 therapy can provide long, durable benefit to a fraction of patients. The on-label PD-L1 test, however, does not accurately predict response. To build a better biomarker, we created a method called T Cell Subtype Profiling (TCSP) that characterizes the abundance of T cell subtypes (TCSs) in FFPE specimens using five RNA models. These TCS RNA models are created using functional methods, and robustly discriminate between naïve, activated, exhausted, effector memory, and central memory TCSs, without the reliance on non-specific, classical markers. TCSP is analytically valid and corroborates associations between TCSs and clinical outcomes. Multianalyte biomarkers based on TCS estimates predicted response to anti-PD-1 therapy in three different cancers and outperformed the indicated PD-L1 test, as well as Tumor Mutational Burden. Given the utility of TCSP, we investigated the abundance of TCSs in TCGA cancers and created a portal to enable researchers to discover other TCSP-based biomarkers.