VSIR and familial pancreatic carcinoma: The other possible reason for the ineffectiveness of immunotherapy in pancreatic cancer is the presence of many highly expressed negative immunoregulatory checkpoints in the TME, like T-cell immunoglobulin and mucin domain-3 (TIM-3), T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) (26), lymphocyte activation gene-3 (LAG-3), and V-domain Ig suppressor of T cell activation (VISTA) (27).