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

Abstract

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-g-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.

Keywords: T cell exhaustion; Tim-3; checkpoint blockade; checkpoint inhibitors; immunotherapy; tumor immunity.

FIGURE 1

Tim-3 serves as a major regulator of immunity in the lymphoid (A) and myeloid (B) compartments. In DCs (dendritic cells), HMGB1 plays a critical role in the transport of nucleic acids into enodosomal vesicles, which is a key step for DCs to sense tumor-derived stress factors or pathogen-associated molecular patterns (PAMPs) and to generate protective immune responses to tumors. In tumor microenvironments, the Tim-3 molecules expressed on the tumor-infiltrating DCs (TADC), bind to HMGB1 to block the transport of nucleic acids into endosomes, thereby suppressing pattern-recognition receptor (PPR)-mediated innate immune responses to tumor-derived nucleic acids. The Interferon-γ production by effector T cells promotes anti-tumor response but also drives expansion of myeloid-derived suppressor cells (MDSC). The latter produce increased Galectin-9 (Gal9) molecules, which then bind to Tim-3 molecules expressed on Tim-3 expressing effector CD8+ T cells in the tumor microenvironment, leading to apoptosis of effector T cells. Further, Tim-3+FoxP3+ Tregs present within the tumor express high amounts of Treg effector molecules (IL-10, etc.) and inhibit effector T cells

FIGURE 2

Expression of ligands for PD-1 and Tim-3 by tumor cells leads to the ligation of PDL1 with PD1 (programmed cell death protein 1) and galectin9 with Tim-3 molecules causing downregulation of T cell function, essentially creating a negative feedback loop that dampens anti-tumor immunity. Co-blockade of both PD-1 and Tim-3 leads to synergistic efficacy and restoration of T cell effector function and tumor cell killing

FIGURE 3

(A) In the absence of ligand-mediated Tim-3 signaling, the Tyr ₂₅₆ and Tyr ₂₆₃ in the C-terminal tail of Tim-3 bind to Bat3. In this state, Bat3 recruits the catalytically active form of Lck, thereby forming an intracellular molecular complex with Tim-3 that preserves and potentially promotes T cell signaling and represses Tim-3-mediated cell death and exhaustion. (B) Interactions between Tim-3 ligands (Galectin 9), and Tim-3 leads to phosphorylation of Tyr ₂₅₆ and Tyr ₂₆₃ and release of Bat-3 from the Tim-3 tail, thereby promoting Tim-3-mediated T cell inhibition by allowing binding of SH2 domain-containing Src kinases (Lck/Fyn/Other proteins) and subsequent regulation of TCR signaling. Because Fyn and Bat3 bind to the same domain in the Tim-3 cytoplasmic tail, a likely molecular switch between Tim-3-Bat3 and Tim-3-Fyn probably triggers the switch of Tim-3 function from being permissive to TCR signaling to inhibition of proximal TCR signaling

FIGURE 4

(A) A tumor with high expression of neoantigens will evoke a strong anti-tumor response, which the tumor evades by upregulating immune-checkpoint ligands (PD-L1, Galectin 9). Monotherapy with anti-PD-1/PD-L1 yields a partial response while a combo therapy with anti-PD-1 plus Tim-3 may be effective in generating a complete response. (B) Following initial tumor regression, there may be delayed tumor relapse following additional mutations in tumor, leading to acquired resistance to further PD-1 blockade. The resistance may be associated with upregulation of Tim-3 or other checkpoint molecules on TILs (tumor-infiltrating lymphocytes). A second-line therapy involving a combo therapy of anti-Tim-3 and an agent targeting resistance pathways or an agonistic antibody to activate co-stimulatory receptors on T cells may efficiently induce an effective anti-tumor response to clear the tumor