The ectonucleotidase CD39 identifies tumor-reactive CD8⁺ T cells predictive of immune checkpoint blockade efficacy in...

Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8⁺ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8⁺ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39⁺ CD8⁺ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39⁺ CD8⁺ T cells. Higher baseline frequency of CD39⁺ CD8⁺ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39⁺ CD8⁺ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8⁺ T cells in human lung cancer.