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.

Keywords: clinical trials as topic; costimulatory and inhibitory T-cell receptors; immunotherapy; tumor microenvironment.

Figure 1

Model of Tim-3 signaling in T cells. In the absence of Tim-3 ligand, Bat-3 is bound to the cytoplasmic tail of Tim-3 and to the catalytically active form of Lck. Lck then phosphorylates the CD3ζ subunit of the T Cell receptor (TCR) complex which is then followed by subsequent recruitment of Zeta-chain-associated protein kinase (ZAP70) to the TCR complex. This recruitment results in the activation of ZAP70/Linker for Activation of T cells (LAT)/Phospholipase C gamma 1 (PLCγ1)/Ca2+ to promote T-cell proliferation and survival. However, Tim-3 ligation by ligand displaces Bat-3 from the Tim-3 tail, resulting in the recruitment of tyrosine phosphatases (CD45 and CD148) which lead to dephosphorylation (inactivation) of Lck, and downregulation of ZAP70/LAT/PLCγ1/Ca2+ TCR signaling and suppression of T-cell proliferation and survival. Bat-3, HLA-B-associated transcript 3; Ceacam1, carcinoembyronic antigen-related cell adhesion molecule-1; Gal-9, galectin-9; Hmgb1, high-mobility group protein B1; PtdSer, phosphatidylserine; Tim-3, T-cell immunoglobulin and mucin domain 3.

Figure 2

Model of Tim-3 signaling in DCs HMGB1 can interact with several receptors either alone or in a complex with DNA or Lipopolysaccharide (LPS). HMGB1 receptors include Receptor for Activated Glycation End products (RAGE), TLR4, TLR2, and IL-1R. HMGB1–DNA complexes bind to RAGE, leading to internalization and activation of TLR9 and TLR7 in the endosome. This leads to the activation of several downstream transcription factors, such as NF-κB, and activation of tumor-associated dendritic cells (TADCs). Tim-3 can sequester HMGB1, resulting in suppression of NF-kB-mediated activation of DCs. Ligation of Tim-3 on DCs also activates Btk and c-Src, which also inhibit the activation of NF-kB. Tim-3-mediated suppression of DCs dampens the production of CXCL9 thereby reducing CD8⁺ T-cell recruitment to the TME. Bat-3, HLA-B-associated transcript 3; Btk, Bruton’s tyrosine kinase; DCs, dendritic cells; HMGB1, high-mobility group protein B1; Tim-3, T-cell immunoglobulin and mucin domain 3; TME, tumor microenvironment.

Figure 3

Model for Tim-3 mAb mechanism of action in AML/MDS. The Tim-3–galectin-9 interaction promotes autocrine leukemic stem cell (LSC) self-renewal. Blockade of the Tim-3–galectin-9 interaction may directly inhibit downstream signaling pathways that foster stem cell self-renewal, including the NF-kB and β-catenin pathways. Alternatively and/or additionally, binding of an anti-TIM-3 antibody to TIM-3 on the surface of LSCs/blasts may facilitate antibody-dependent cellular phagocytosis (ADCP) by myeloid cells/macrophages expressing FcγRs and promotion of M1 phenotype. Tim-3, T-cell immunoglobulin and mucin domain 3.