Tim-3, a negative regulator of anti-tumor immunity

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T cell immunoglobulin-3 (Tim-3) was identified nearly 10 years ago as a negative regulator of IFN-γ-secreting CD4+ T helper 1 and CD8+ T cytotoxic 1 cells. Tim-3 is now classed with other inhibitory receptors, such as cytotoxic lymphocyte antigen-4 and programmed death-1 that are commonly referred to as immune checkpoint molecules. Recent studies have highlighted Tim-3 as an important player in the CD8+ T cell exhaustion that takes place in chronic immune conditions such as chronic viral infection and cancer in both humans and experimental models. In addition to its role in exhausted T cells, recent data suggest that Tim-3 can further influence cancer outcome through its action on myeloid cells and cancer stem cells.

Highlights

► Tim-3 is expressed on exhausted CD8+ T cells in cancer. ► Tim-3 may influence tumor immunity through its actions on myeloid cells. ► Tim-3 is expressed on cancer stem cells and may have a role in cancer initiation. ► Tim-3 expression is enriched in T cells in tumor tissue. ► Tim-3 is an attractive immunotherapeutic candidate for clinical translation.

Introduction

The immune response has developed self-regulatory mechanisms to prevent the untoward immune-driven pathology that ensues when immune responses go unchecked. One of these mechanisms is the upregulation of negative regulatory or immune checkpoint molecules, such as cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), on activated T cells. These molecules turn off T cell responses by different mechanisms such as interfering with T cell co-stimulation (CTLA-4) or abrogating signaling through the T cell receptor (PD-1). T cell immunoglobulin-3 (Tim-3) was discovered in 2002 and differs from other immune checkpoint molecules in that it is not upregulated on all T cells post-activation but rather is specifically upregulated only on T cells that have differentiated to produce IFN-γ, CD4+ T helper 1 and CD8+ T cytotoxic 1 (Tc1) cells [1]. Exposure to the Tim-3 ligand, galectin-9, triggers cell death in Tim-3+ T cells [2]. Therefore, Tim-3 specifically terminates immune responses driven by IFN-γ-secreting CD4+ and/or CD8+ T cells.

It has been noted that dysregulated and sustained expression of immune checkpoint molecules marks the impaired or exhausted T cells that exist in chronic disease states such as cancer. Indeed, Tim-3 expression has recently been reported on exhausted T cells in both human cancer and in preclinical models of cancer [3••, 4•, 5••, 6•]. In addition, Tim-3 has a role in promoting myeloid-derived suppressor cells (MDSC) [7••] and regulating the cytokine response in myeloid cells [8••]. Lastly, Tim-3 expression has recently been demonstrated in cancer stem cells [9••, 10••] and lymphoma-associated endothelium [11••]. Thus, Tim-3 can function as a determinant of both the anti-tumor immune response and the development of cancer at multiple levels.

Section snippets

Tim-3 in T cell exhaustion in cancer

T cell exhaustion is a state of T cell impairment that develops in chronic immune conditions and was initially described in chronic lymphocytic choriomeningitis virus infection in mice [12]. T cell exhaustion is now known to occur in chronic viral infection in humans and in cancer (reviewed in [13]). Exhausted T cells fail to proliferate and exert effector functions such as cytotoxicity and cytokine secretion in response to antigen stimulation. Furthermore, exhaustion is a progressive process

Other roles for Tim-3 in tumor immunity

While the role of Tim-3 in T cell exhaustion has taken center stage, emerging data suggest that Tim-3 may impact on anti-tumor immunity in other ways. The expression of Tim-3 on T cells has been shown to promote granulocytic MDSC via a cognate interaction with galectin-9, which is expressed at high levels on CD11b+Ly-6G+ cells [7••]. Given that MDSC expand to large numbers in tumor-bearing hosts, are potent suppressors of T cell responses, and that their presence is correlated with poor

Potential role for Tim-3 in tumor-formation

Two recent studies have identified Tim-3 expression on leukemic stem cells (LSC) in patients with acute myeloid leukemia (AML) [9••, 10••]. Tim-3+ AML cells were found to reconstitute AML and anti-human Tim-3 antibody blocked AML engraftment in a xenotransplant model. The fact that Tim-3 is expressed at high levels on LSC but not hematopoietic stem cells makes Tim-3 an attractive candidate for eradication of human AML. Whether Tim-3 is also expressed on cancer stem cells in other nonhematologic

Clinical application of anti-Tim-3 immunotherapy

Blockade of immune checkpoint molecules is currently at the forefront of cancer immunotherapy due to the success and recent United States Food and Drug Administration (FDA) approval of anti-CTLA-4 (Ipilimumab) for treatment of advanced melanoma that is refractory to standard of care treatments. However, the untoward autoimmune toxicity associated with anti-CTLA-4 treatment [26] has provided impetus for the evaluation and development of reagents that target other immune checkpoint molecules.

Conclusion and future perspectives

Tim-3 is an immune checkpoint molecule that was originally described as a negative regulator of IFN-γ producing CD4+ and CD8+ T cells. This negative regulatory role has now been extended to include both direct (T cell exhaustion) and indirect (promotion of MDSC, regulation of cytokine response in myeloid cells, expression on tumor-associated endothelium) mechanisms. Furthermore, Tim-3 may influence cancer development directly via its expression on cancer stem cells. These potential multiple

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The author wishes to thank Kaori Sakuishi and Vijay K. Kuchroo for critical reading of this manuscript.

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