2.4 TIM-3 (T cell Immunoglobulin and Mucin-domain containing-3)
TIM-3 (T cell Immunoglobulin and Mucin-domain containing-3), discovered
in 2002, is a member of the TIM family of immunoregulatory proteins
[104, 105]. TIM member family protein is characterized by a common
structural organization that includes an amino-terminal immunoglobulin
variable domain (IgV domain) with five noncanonical cysteines, a mucin
stalk, a trans-membrane domain, and a cytoplasmic tail [105].
Nuclear factor of activated T cells (NFAT) signaling has been
demonstrated to influence the regulation of Tim-3 in CD8+ T cells
[106]. Tim-3 expression is also regulated by at least three
transcription factors: NFIL3, T-bet, and STAT3 [107].
TIM-3 is an inhibitory receptor expressed on various IFNγ-producing
immune cells, including CD4 + T cells, CD8 + T cells,, natural killer
(NK) cells, FoxP3 + Treg cells, dendritic cells, macrophages and
monocytes [108, 109]. TIM-3 plays a critical role in regulating
immune responses and maintaining immune homeostasis. It is involved in
suppressing immune responses and inducing immune tolerance, primarily by
depleting CD8( +) T-cells. While this function can help prevent
autoimmunity, it is detrimental in the context of cancer [105, 108,
110]. TIM-3 protein also has a role in efferocytosis [111, 112].
Fourcade et al. observed that in melanoma patients, the upregulation of
Tim-3, in conjunction with PD-1, results in a subset of CD8+ T cells
that are highly non-responsive [113].
TIM-3 interacts with several ligands, the most well-studied of which is
galectin-9 (gal-9). Other ligands include phosphatidylserine (PtdSer),
high mobility group protein B1 (HMGB1), and, cancer-embryonic antigen
cell adhesion molecule 1 (CEACAM1) [105, 107]. These ligands attach
to different regions on the TIM-3 extracellular immunoglobulin V domain
[105, 107, 114]. The interaction between TIM-3 and its ligands
transmits inhibitory signals to immune cells, leading to the suppression
of their activation and effector functions [107]. For instance, the
binding of galectin-9 to TIM-3 on T cells can induce cell death or
exhaustion, a state where T cells lose their ability to proliferate and
produce cytokines in response to antigen stimulation [115].
In cancer, TIM-3 expression is often upregulated on T cells within the
TME. This upregulation contributes to the immune evasion mechanisms of
tumors by suppressing the anti-tumor immune response. High levels of
Tim-3 expression are associated with the suppression of T cell responses
and T cell dysfunction, also known as T cell exhaustion, which is a
gradual loss of T cell function in a hierarchical manner during tumor
development [114]. TIM-3 activates the IL-6-STAT3 pathway, which
directly suppresses CD4+ T cells and inhibits Th1 polarization
(development [114]. TIM-3 is also expressed on other immune cells in
the TME, including Tregs and myeloid-derived suppressor cells (MDSCs),
further contributing to an immunosuppressive environment [116].
Blocking TIM-3 has emerged as a promising strategy to rejuvenate
exhausted T cells and enhance anti-tumor immunity [114]. By
inhibiting the interaction between TIM-3 and its ligands, TIM-3 blockade
can restore the function of exhausted T cells, increasing their
proliferation, cytokine production, and cytotoxic activity. Preclinical
studies have shown that TIM-3 blockade can enhance anti-tumor immunity.
A study by Ngiow et al. observed that anti-mouse TIM-3 monoclonal
antibodies (mAb) used against experimental and carcinogen-induced tumors
enhance CD8+ and CD4+ T cells IFN-γ-mediated antitumor immunity and
suppress established tumors [117]. A study by Kikushige and
Miyamoto, in xenograft models reconstituted with human acute myeloid
leukemia leukemic stem cells (AML LSCs) or hematopoietic stem cells
(HSCs), a TIM-3 mouse IgG2a antibody with cytotoxic activities
eliminated AML LSCs in vivo, while preserving normal human hematopoiesis
[118].
When used in combination with other ICIs, such as PD-1/PD-L1 inhibitors,
TIM-3 blockade has demonstrated synergistic effects [119]. The
rationale for this combination therapy is that targeting multiple
inhibitory pathways can produce a more comprehensive and potent
reactivation of T cells. PD-1/PD-L1 inhibitors lift the suppression
mediated by the PD-1 pathway, while TIM-3 blockade further enhances T
cell function by targeting a different inhibitory mechanism [120,
121]. Sakuishi et al. observed that T cells expressing Tim-3 also
co-express PD-1, with Tim-3+ PD-1+ TILs representing the predominant
fraction of T cells infiltrating tumors, in mice bearing solid tumors.
These Tim-3(+)PD-1(+) TILs display the most profound exhausted phenotype
characterized by an inability to proliferate and produce IL-2, TNF, and
IFN-γ. Their research also documented that simultaneous targeting of the
Tim-3 and PD-1 pathways reverses T cell exhaustion and restores
anti-tumor immunity more effectively than targeting either pathway alone
[119]. In their study, Zhou et al. identified a distinct phenotype
of exhausted T cells in mice with advanced acute myelogenous leukemia
(AML), characterized by concurrent expression of Tim-3 and PD-1. This
co-expression escalated as AML advanced. PD-1+ Tim-3+ CD8+ T cells
exhibited impaired production of IFN-γ, TNF-α, and IL-2 in response to
AML cells expressing PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9).
Zhou et al. further demonstrated that individually blocking the
PD-1/PDL1 or Tim-3/galectin-9 pathway failed to rescue mice from
AML-induced mortality. However, a synergistic effect was observed in
reducing tumor burden and mortality when both pathways were
simultaneously targeted [122]. In a work by Fourcade et al., dual
blockade of PD-1 and Tim-3 enhanced the expansion and cytokine
production of vaccine-induced CD8(+) T cells in vitro [123]. In a
murine model of ovarian cancer, Guo et al. noted that either anti-TIM-3
or CD137 mAb alone was unable to prevent tumor progression in mice
bearing established tumor, however, combined anti-TIM-3/CD137 mAb
significantly inhibited the growth of these tumors with 60% of mice
tumor free 90 days after tumor inoculation. Therapeutic efficacy was
associated with a systemic immune response with memory and antigen
specificity [124].
Ongoing clinical trials are assessing the safety and efficacy of TIM-3
inhibitors, both as standalone treatments [ NCT04823624,
MBG453] [ NCT04623892, TQB2618]
[ NCT03489343, Sym023], and in combination with other checkpoint
inhibitors [ NCT03680508, TSR-022 (cobolimab, TIM-3 binding
antibody) and TSR-042 (dostarlimab, PD-1 binding antibody)] [ NCT04139902, anti-PD-1/anti-TIM-3 combination (TSR-042 /
TSR-022)] [ NCT03708328, TIM-3/PD-1] . The results
of these trials will provide important insights into the potential of
TIM-3 inhibitors as a new class of immunotherapies.