Even if T cells are successful in penetrating the tumor bed, they still face a battery of obstacles, including suppressive immune infiltrate comprising Treg cells, MDSCs, TAMs, tumor-associated neutrophils, and immature DCs; suppressive molecules (e.g., TGF-β); suppressive ligands (i.e., PD-L1/L2, VISTA) competition for and/or downregulation of co-stimulatory ligands; and T cell-intrinsic regulatory mechanisms, including PD-1 and CTLA-4 upregulation, and then ultimately exhaustion or anergy [41, 91, 119, 128, 201] (as described above). The gene discussed is VSIR; the disease is neoplasm.