Tim-3 finds its place in the cancer immunotherapy landscape

Abstract

The blockade of immune checkpoint receptors has made great strides in the treatment of major cancers, including melanoma, Hodgkin’s lymphoma, renal, and lung cancer. However, the success rate of immune checkpoint blockade is still low and some cancers, such as microsatellite‐stable colorectal cancer, remain refractory to these treatments. This has prompted investigation into additional checkpoint receptors. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a checkpoint receptor expressed by a wide variety of immune cells as well as leukemic stem cells. Coblockade of Tim-3 and PD-1 can result in reduced tumor progression in preclinical models and can improve antitumor T-cell responses in cancer patients. In this review, we will discuss the basic biology of Tim-3, its role in the tumor microenvironment, and the emerging clinical trial data that point to its future application in the field of immune-oncology.

Transforming growth factor beta type 1 (TGF-β) and hypoxia-inducible factor 1 (HIF-1) transcription complex as master regulators of the immunosuppressive protein galectin-9 expression in human cancer and embryonic cells

“…When complexed with Tim-3 on the cell surface, galectin-9 induces downstream signalling of differential intensity [8][9][10], depending on the type of human myeloid and lymphoid cells [11]. In myeloid cells, galectin-9 primarily triggers growth factor type responses, while in lymphoid cells it induces proapoptotic signalling [10][11][12][13]. Galectin-9, together with Tim-3, can be shed from the cell surface by proteolytic enzymes, thus being released into the tumour microenvironment or blood [2].…”

Immune Checkpoint Molecules—Inherited Variations as Markers for Cancer Risk

“…In silico analysis of 5’ upstream and the promoter region of HAVCR2 gene predicted localization of putative binding sites for the TFs: GATA-1, YY-1, p300, HNF-3b, Pbx-1, RARa, NFE2, MZF-1, and GATA-3 ( 57 ). The T-bet and NFIL3 (Nuclear Factor, Interleukin 3 Regulated) TFs have been reported as being involved in the regulation of HAVCR2 gene in T cells ( 224 ).…”

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

“…The authors also suggested that the TME could be directly affected by TIM-3, which leads to decreased immune surveillance and tumour clearance [ 276 ]. Preclinical data pointed out the relevance of blocking TIM-3 together with PD-1, in particular, in several cancer models [ 277 ]. These data led to the clinical development of TIM-3 antibodies, which are being tested in combination with anti-PD-1/L1 mAbs.…”