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.

Keywords: HMGB1; Immunocheckpoint inhibitors; T cell immunoglobulin and mucin domain 3; TIM-3; immunotherapy; melanoma.

Figure 1

Articles selection and flowchart of the review.

Figure 2

(A) Photomicrograph showing an example of immunostaining for TIM-3 in a malignant melanoma specimen. Note the broad positivity of the brown signal at the level of both the neoplastic cells and the TME (Immunostaining for TIM-3, Original Magnification 4×). (B) Immunohistochemical preparation for TIM-3: note, in more detail, the strong and widespread cytoplasmic positivity of melanoma cells for TIM-3, as well as the presence of positive cells in the TME. Although no data is available in the literature yet, and our data have not yet been published, this expression pattern fits well with the concept of ‘pleiotropism’ specific to TIM-3 (Immunostaining for TIM-3, Original Magnification 10×).