While a previous study showed that addition of anti-CTLA-4 to anti-PD-L1 enhanced activation of CD4+ T cells in HNSCC,48 this combination unexpectedly led to the expansion of tumor-associated regulatory T cells (Tregs) due to disruption of a CTLA-4-dependent feedback loop, which may limit the overall therapeutic efficacy.49 The gene discussed is CD274; the disease is head and neck squamous cell carcinoma.