In this issue of the JCI, Duhen et al. (11) profiled the tumor immune microenvironment in patients with HPV+ head and neck squamous cell carcinoma (HNSCC) or microsatellite-stable colorectal carcinoma (CRC) and identified a subset of CD4+ Th cells coexpressing the immune checkpoint and costimulatory molecules programmed cell death 1 (PD-1) and ICOS. The gene discussed is PDCD1; the disease is head and neck squamous cell carcinoma.