TIM-3, a Possible Target for Immunotherapy in Cancer and Chronic Viral Infections

Review Article

Austin Virol and Retrovirology. 2014;1(2): 6.

TIM-3, a Possible Target for Immunotherapy in Cancer and Chronic Viral Infections

Roger Tieu1, Praveen Kumar Amancha1, François Villinger1,2 and Siddappa N. Byrareddy2*

1Division of Microbiology and Immunology, Yerkes National Primate Research Center, USA

2Department of Pathology & Laboratory Medicine, Emory University School of Medicine, USA

*Corresponding author: Siddappa N. Byrareddy, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, 101 Woodruff Circle, WMRB, Room 2337A, Atlanta, GA 30322

Received: November 06, 2014; Accepted: December 03, 2014; Published: December 05, 2014


Effector T-cell responses are controlled by complex mechanisms involving various soluble factors and co-stimulatory and co-inhibitory molecules. These inhibitory receptors act as immune checkpoints and are extensively investigated as possible therapeutic targets, such as PD-1 and CTLA-4. Recently TIM-3 is also gaining prominence in tumor and chronic viral infection models as a candidate for immunotherapy in conjunction with other inhibitory receptors. This review discusses the recent findings on the expression of TIM-3 and its ligand in tumor and chronic viral infection.

Keywords: TIM-3; CTLA-4; Immunotherapy; Galectin-9


Upon exposure to non-self entities such as pathogens, a number of receptors including Pattern Recognition Receptors (PRRs) are triggered leading to a rapid response of the innate immune system [1]. This initial response paves the way for the elaboration of pathogen specific adaptive humoral and cell mediated responses via a complex network of co-stimulatory and inhibitory signals. The initial efferent response by and large favors co-stimulatory signaling for the activation and proliferation of effector cells with the intent of eliminating the invading pathogen. After controlling or eliminating the threat, the absence of continuing antigen stimulation leads to elimination of most effector cells via apoptosis while a fraction of these cells become long term memory cells and homeostasis is reestablished. However, during the course of cancer and chronic persisting viral infections, this return to normalcy is perturbed leading to immune dysfunction and dysregulation resulting in the continued presence of effector cells with poor function. The mechanisms leading to such muted phenotype are increasingly being characterized and involve the expression of receptors, which are thought to play a central role in this inhibition of function.

These inhibitory mechanisms are an integral and critical contributor to immune homeostasis, in minimizing collateral damage during extended inflammatory response as well as preventing autoimmunity by maintaining peripheral self-tolerance. Such pathways serve to restrain effector cell activity, mainly of T cells. Inappropriately activated lymphocytes recognizing self-antigen subsequently lose effector function and undergo apoptosis or energy. Such responses require constricted regulation and transient expression of inhibitory signaling. Prolonged and/or over expression of multiple inhibitory receptors have been associated with impaired immune function such as T cell exhaustion, a state characterized by poor effector function, a mechanism that is exploited by many persistent pathogens.

During chronic active infections, a progressive loss of function in pathogen-specific CD8+ T cells was documented following a hierarchy with an initial impaired production of IL-2 and cytotoxicity, followed by loss of TNF-α, and eventually IFN-γ at late stages [2], resulting in a condition known as exhaustion [2,3] (Figure 1). T cell exhaustion has been found to be associated with the up-regulation of inhibitory receptors in concert with their ligands also up-regulated on Antigen Presenting Cells (APCs) [3]. The initial marker associated with inhibition of function has been Cytotoxic T Lymphocyte Associated Antigen-4 (CTLA-4), a marker upregulated on the surface of activated T cells, with markedly higher affinity for CD80/CD86, the co-stimulatory ligands to CD28 during the elaboration of an antigen specific response [4]. More recently, PD-1 (programmed death 1) was found to be selectively up-regulated by exhausted T cells during murine chronic LCMV (Lymphocytic Choriomeningitis Virus) infection, and blocking of this receptor with antibodies enhanced virus-specific CD8+ T cell response and decreased viral load [5]. This finding defined a novel role for inhibitory pathway involvement in controlling T cell response in chronic viral infection as well as the potential for targeting these same pathways. However, blockade of the PD-1 pathway only partially restored T cell functions, suggesting the involvement of other inhibitory pathways. Additional inhibitory receptors have been since identified which include T cell immunoglobulin and mucin domain 3 (TIM-3), CD244 (2B4), killer Cell Lectin like Receptor G1 (KLRG1), and Lymphocyte Activation Gene 3 (LAG3) [6-12].

Citation: Tieu R, Amancha PK, Villinger F and Byrareddy SN. TIM-3, a Possible Target for Immunotherapy in Cancer and Chronic Viral Infections. Austin Virol and Retrovirology. 2014;1(2): 6. ISSN:2472-3517