We favor the idea that the most important factor reducing the cytotoxic potential of CD8+ T-cells is associated with the lack of a “direct contact” with HLA-I negative target tumor cells due to an exclusive localization in the “stroma”, which creates a physical barrier between the HLA-I negative tumor cells and the infiltrating leucocytes/macrophages (see Figure 2b). The gene discussed is CD8A; the disease is neoplasm.