Blocking monoclonal antibodies of TIM proteins as orchestrators of anti-tumor immune response (1)
T cell immunoglobulin and mucin domain (TIM) proteins are type-I cell-surface molecules that share a unique structure, including an N-terminal immunoglobulin (Ig)-like domain, a mucin domain with O-linked and N-linked glycosylation, a single transmembrane domain, and a cytoplasmic region with tyrosine phosphorylation motifs, except in TIM-4.
TIM-1 acts as a co-stimulatory molecule for T cell activation, while others suggest a role for TIM-1 as an immune checkpoint which inhibits T cell activities. The therapeutic effects of these mAbs were tested in a variety of murine models of allergic and autoimmune diseases. The administration of agonistic anti-TIM-1 mAbs in vivo results in enhanced inflammation, e.g., pulmonary inflammation, accelerates reject of transplanted xenografts, and worsen the severity of autoimmune diseases. The administration of antagonistic anti-TIM-1 mAbs results in a significant decrease in inflammation such as asthma and allergy, and helps to attenuate inflammation in autoimmune disease and cisplatin-induced nephrotoxicity. Agonistic mAbs of TIM-1 are expected to trigger or amplify antitumor immune responses through the enhancement of infiltration and proliferation by lymphocytes and the production of proinflammatory cytokines, but may increase the risks of worsening tumor-induced inflammation. On the other hand, antagonistic mAbs may be used to attenuate inflammation and prevent inflammation-related tumor progression. However, the therapeutic effects of anti-TIM-1 mAbs should be carefully evaluated in transplant and naturally occurring tumor models.
TIM-3 is shown to be expressed on a wide variety of immune cells, including dendritic cells, macrophages, natural killer (NK) cells, T cells, B cells, and non-immune cells such as epithelial cells, endothelial cells and stromal cells. TIM-3 expression is induced in innate immune cells, e.g., dendritic cells and macrophages, by tumor-released factors such as interleukin (IL)-10 and vascular endothelial growth factor, leading to a suppression of innate responses to nucleic acids released from apoptotic tumor cells by interacting with HMGB1. The expression of TIM-3 in innate and adaptive immune cells, in addition to tumor cells, makes it an attractive target to enhance immune responses against tumors or to eradicate TIM-3-expressing cancer stem cells.
TIM-4 lacks the putative tyrosine phosphorylation sequence in its intracellular domain that is implicated in signaling by other TIMs, which suggests a role for TIM-4 as a binding receptor more than a signaling receptor. TIM-4 is expressed exclusively in antigen presenting cells (APCs) such as dendritic cells and macrophages, where it serves as a binding receptor of phosphatidylserine (PS) and enhances the engulfment of apoptotic cells. Blockade by anti-TIM-4 mAbs serves as a promising strategy in cancer therapy, in particular to enhance tumor antigen-specific T cell responses. In this regard it is also of great interest to evaluate the effects of anti-TIM-4 mAbs on the functions of central and effector memory T cells in future studies.
TIM family molecules as key players for the regulation of innate and adaptive immune response in the tumor microenvironment. TIM-3 and TIM-4 expression are highly induced in dendritic cells and macrophages in tumors. TIM-3 inhibits innate immune responses mediated by DAMPs, while TIM-4 suppresses antigen-specific responses by repressing presentation of immunogenic tumor-associated antigens and establishing tolerated tumor environments.
