The study investigates the predictive value of an IFN-γ-related mRNA profile for clinical response to PD-1 checkpoint blockade therapy. The researchers analyzed gene expression profiles from baseline tumor samples of patients treated with pembrolizumab, a PD-1 inhibitor. They identified immune-related signatures that correlated with clinical benefit, starting with a small pilot of 19 melanoma patients and expanding to 220 patients with nine different cancers. The T cell-inflamed gene expression profile (GEP) contained genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance. This profile was independently confirmed and compared with PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP has been developed into a clinical-grade assay and is being evaluated in ongoing pembrolizumab trials. The study suggests that a T cell-inflamed microenvironment, characterized by active IFN-γ signaling and T cell-related biology, is a common feature of tumors responsive to PD-1 checkpoint blockade.The study investigates the predictive value of an IFN-γ-related mRNA profile for clinical response to PD-1 checkpoint blockade therapy. The researchers analyzed gene expression profiles from baseline tumor samples of patients treated with pembrolizumab, a PD-1 inhibitor. They identified immune-related signatures that correlated with clinical benefit, starting with a small pilot of 19 melanoma patients and expanding to 220 patients with nine different cancers. The T cell-inflamed gene expression profile (GEP) contained genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance. This profile was independently confirmed and compared with PD-L1 immunohistochemistry in 96 patients with head and neck squamous cell carcinoma. The T cell-inflamed GEP has been developed into a clinical-grade assay and is being evaluated in ongoing pembrolizumab trials. The study suggests that a T cell-inflamed microenvironment, characterized by active IFN-γ signaling and T cell-related biology, is a common feature of tumors responsive to PD-1 checkpoint blockade.