Tim‐3 and its role in regulating anti‐tumor immunity

Abstract

Summary Immunotherapy is being increasingly recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA-4 and PD-1 have achieved durable responses in melanoma, renal cancer, Hodgkin’s diseases and lung cancer. However, the success rate of these treatments has been low and a large number of cancers, including colorectal cancer remain largely refractory to CTLA-4 and PD-1 blockade. This has provided impetus to identify other co-inhibitory receptors that could be exploited to enhance response rates of current immunotherapeutic agents and achieve responses to the cancers that are refectory to immunotherapy. Tim-3 is a co-inhibitory receptor that is expressed on IFN-γ-producing T cells, FoxP3+ Treg cells and innate immune cells (macrophages and dendritic cells) where it has been shown to suppress their responses upon interaction with their ligand(s). Tim-3 has gained prominence as a potential candidate for cancer immunotherapy, where it has been shown that in vivo blockade of Tim-3 with other check-point inhibitors enhances anti-tumor immunity and suppresses tumor growth in several preclinical tumor models. This review discusses the recent findings on Tim-3, the role it plays in regulating immune responses in different cell types and the rationale for targeting Tim-3 for effective cancer immunotherapy.

The immune checkpoint CD96 defines a distinct lymphocyte phenotype and is highly expressed on tumor‐infiltrating T cells

“…One feasible approach is to identify and block additional inhibitory receptors on hyporesponsive CD8 + T cells to augment antitumor function. Additional inhibitory receptors such as TIM‐3, LAG‐3, BTLA, Vista and B7‐H4 have been identified on chronically stimulated T cells and antibodies that block the respective ligands suggest these pathways contribute to CD8 + T‐cell dysfunction in functionally independent manners . Recent preclinical studies have identified CD96 and TIGIT as co‐inhibitory Ig superfamily receptors which function on lymphocytes to counterbalance the costimulatory CD226.…”

TIM-3 expression in breast cancer

“…TIM-3 mediates its suppressive activity on immune cells via its ligands that include phosphatidylserine, CEACAM-1 and the widely expressed ligand galectin-9 23,24 . TIM-3 is expressed on activated T cells and its signaling on cytotoxic T cells leads to an exhausted phenotype, characterized by a reduction in proliferation, decreased production of effector cytokines and apoptosis of effector T cells 25 . In addition, TIM-3+ TILs can co-express PD-1, with blockade of both receptors leading to a more pronounced tumor regression than either agent alone, at least in pre-clinical studies 26,27 .…”

Monoclonal antibody against human Tim‐3 enhances antiviral immune response

“…Antibodies against CTLA‐4 and PD‐1 have been used to treat many immune disorders . Tim‐3 is considered a next‐generation checkpoint inhibitor with therapeutic potential . A previous report has shown that Tim‐3 expression is significantly upregulated in patients who are resistant to PD‐1 antibody treatment .…”