Under chronic antigen stimulation, tumor specific CD8+ T cells continue to overexpress PD-1, leading to functional inhibition and epigenetic reprogramming, which is characterized by loss of effector function, reduced proliferation and co expression of multiple inhibitory receptors, such as T cell immunoglobulin and mucin domain containing protein 3 (Tim-3) and lymphocyte activating gene 3 (LAG-3) [48,49]. Here, HAVCR2 is linked to neoplasm.