Which characteristic best predicts response to checkpoint inhibitors?

• A. High PD-L1 expression alone.
• B. Low T cell infiltration.
• C. Absence of neoantigens.
• D. High T cell infiltration and IFN-gamma signature.

Answer: (D)

The best predictor is a T cell–inflamed tumor microenvironment, indicated by high T cell infiltration and an IFN-gamma–driven gene signature. Checkpoint inhibitors work by lifting the brakes on existing anti-tumor T cells, so tumors that already have robust T cell presence (often CD8+ T cells) and a signaling environment dominated by IFN-gamma are most likely to respond, because there are active T cells that can be reinvigorated to attack cancer cells. The IFN-gamma signature reflects ongoing immune activity, including upregulation of antigen presentation and chemokines that support T cell function, which further enhances the effect of checkpoint blockade.

High PD-L1 expression alone isn’t enough to predict response because PD-L1 can be upregulated for various reasons and doesn’t always correspond to productive T cell activity. A tumor with few T cells—the so-called “cold” tumor—offers little substrate for checkpoint inhibitors to unleash, leading to poor responses. Absence of neoantigens would limit the immune system’s ability to recognize cancer cells, also reducing likelihood of response. Thus, the combination of strong T cell infiltration and an IFN-gamma–related program best forecasts responsiveness.