Conversely, smoking/drinking-related HPV-negative HNSCC is most often characterized by an impaired local and general immune response, dysfunction of immunocompetent cells, i.e., CD3+ zeta chain T cells (CD3ζ), CD8+ IFN-γ T cells (CTLs), CD45+ cells, CD19+/CD20+ B cells, APCs/DCs and MDSCs, and increased intra-tumour infiltration of regulatory T cells, dysfunctional CD56dim NK cells, increased CD4+CD25+Foxp3+Treg/ CD8+ T (CTLs) cell ratio and increased T cell exhaustion markers, i.e., PD-1, CTLA-4, TIM-3, LAG-3, IDO-1, KIR and TIGIT [121,304]. The gene discussed is CD4; the disease is head and neck squamous cell carcinoma.