T Cell Immunoglobulin and Mucin Domain 3 (TIM-3) in Cutaneous Melanoma: A Narrative Review

Abstract

T cell immunoglobulin and mucin domain 3 (TIM-3) is an inhibitory immunocheckpoint that belongs to the TIM gene family. Monney et al. first discovered it about 20 years ago and linked it to some autoimmune diseases; subsequent studies have revealed that some tumours, including melanoma, have the capacity to produce inhibitory ligands that bind to these receptor checkpoints on tumour-specific immune cells. We conducted a literature search using PubMed, Web of Science (WoS), Scopus, Google Scholar, and Cochrane, searching for the following keywords: “T cell immunoglobulin and mucin-domain containing-3”, “TIM-3” and/or “Immunocheckpoint inhibitors” in combination with “malignant melanoma” or “human malignant melanoma” or “cutaneous melanoma”. The literature search initially turned up 117 documents, 23 of which were duplicates. After verifying eligibility and inclusion criteria, 17 publications were ultimately included. A growing body of scientific evidence considers TIM-3 a valid inhibitory immuno-checkpoint with a very interesting potential in the field of melanoma. However, other recent studies have discovered new roles for TIM-3 that seem almost to contradict previous findings in this regard. All this demonstrates how common and valid the concept of ‘pleiotropism’ is in the TME field, in that the same molecule can behave completely or partially differently depending on the cell type considered or on temporary conditions. Further studies, large case series, and a special focus on the immunophenotype of TIM-3 are absolutely necessary in order to explore this highly promising topic in the near future.

Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy

“…To date, TIM-3 has been found to be expressed on T cells (except for Th2 cells), and other immune cells, such as NK cells, macrophages, DCs, myeloid-derived suppressor cells, and mast cells. Moreover, TIM-3 is also expressed on certain malignant cells, such as melanoma [ 39 , 40 ], myeloid leukemia [ 41 ], non-small cell lung cancer (NSCLC) [ 42 ], prostate cancer [ 43 ], osteosarcoma [ 44 ], colon carcinoma [ 45 ], and hepatocellular carcinoma (HCC) cells [ 46 ]. When TIM-3 binds to a ligand, immune cell or adaptive immune cell maturation and activation is attenuated, which is beneficial to tumor cell proliferation and survival.…”