In this issue of the JCI, Duhen et al. analyzed tumors from patients with head and neck squamous cell carcinoma or colon carcinoma and identified a unique programmed cell death 1–positive, ICOS1-positive (PD-1+ICOS1+) subpopulation of CD4+ TILs highly enriched for the ability to recognize tumor-associated antigens. The gene discussed is CD4; the disease is colon carcinoma.