TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action (1)

T cell immunoglobulin and mucin domain 3 (TIM-3) has been recognized as a member of the TIM gene family, which includes TIM-1, TIM-3, TIM-4 in humans and Tim-1-8 in mice. T cell TIM-3 has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. TIM-3 is expressed on Th1, Th17, CD8+ T cells–cells of myeloid lineages in mice. Engagement between TIM-3 and its ligands has been found to suppress Th1 and Th17 responses and induce peripheral immune tolerance, supporting an inhibitory role of TIM-3 in T cell-mediated immune responses.

The TIM family is composed of type I membrane proteins, which share a similar structure: a variable immunoglobulin domain (IgV), a glycosylated mucin domain of varying length in the extracellular region, and a single transmembrane domain. Four relevant ligands have been shown to interact with the IgV domain of TIM-3. These include galectin-9 (Gal-9), high mobility group protein B1 (HMGB1), carcinoembryonic antigen cell adhesion molecule 1 (Ceacam-1), and phosphatidylserine (PtdSer). TIM-3 is highly expressed on tumor infiltrating DCs and actively competes with nucleic acids released from dying tumor cells to bind HMGB1, effectively inhibiting stimulation of the innate immune response by nucleic acids. As a result, activation of innate immunity and production of pro-inflammatory cytokines can be attenuated.

TIM-3 was also shown to be expressed in tumor infiltrating lymphocytes (TIL) or tumor antigen-specific T cells in peripheral blood from many cancer types such as hepatocellular cancer, cervical cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer (NSCLC), head and neck cancer, renal cell carcinoma (RCC), gastric cancer, esophageal cancer, prostate cancer, and non-Hodgkin lymphoma. TIM-3 has been shown to be upregulated in TIL in mouse tumor models such as CT26 colon adenocarcinoma, 4T1 mammary adenocarcinoma, and B16F10 melanoma. A combination of TIM-3 and PD-1 mAbs had a much greater antitumor effect than administration of TIM-3 or PD-1 mAbs alone. TIM-3 mAbs injection slowed tumor progression in many mouse tumor models, such as MC38 colon carcinoma, WT3 sarcoma, CT26 colon adenocarcinoma, and TRAMP-C1 prostate tumor. combination of TIM-3 mAbs and CTLA4 mAbs, or TIM-3 mAbs and PD-1 mAbs has had much greater antitumor effects.

TIM-3 signaling directly regulates the function of Th1 and CD8+ T cells through various mechanisms. TIM-3 is an exhaustion marker for Th1 cells. A substantial proportion of CD4+TIM-3+ TIL are Foxp3+, suggesting a role for TIM-3 in Treg within the tumor microenvironment (TME). TIM-3 has also been found in many tissue-resident Tregs, and plays an important role in both maintaining immune tolerance as well as tissue repair. TIM-3 marks NK cells with greater effector function, including cytokine production and cytotoxicity. However, cross-linking of TIM-3 inhibits NK cell-mediated cytotoxicity, suggesting that interaction of TIM-3 with one or more of its ligands negatively regulates NK cell activity. TIM-3 might play both stimulatory and inhibitory roles in NK cells, depending on cellular and pathological context.

TIM-3 has been shown to be expressed by various myeloid cells (e.g., DCs, monocytes, and macrophages), and to play an important role in regulating innate immune cell-mediated anti-viral infection and antitumor immune responses. The exact role of TIM-3 is dependent on the type of DC where it is expressed and the specific ligand through which it primarily engages these cells.

TIM-3-specific mAbs and TIM-3 overexpression in macrophages inhibited TLR4-stimulated inflammatory cytokine production and promoted sepsis in vivo. TIM-3 acts as a negative regulator of macrophages and monocytes during innate immune responses, and interaction of Gal-9 and TIM-3 resulted in the activation of macrophages and promoted antibacterial activity, though still-undefined mechanisms.

1. W. Du, M. Yang, A. Turner, C. Xu, R. L. Ferris, J. Huang, L. P. Kane, B. Lu, TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action. Int. J. Mol. Sci. 18 (2017), doi:10.3390/ijms18030645.