2. Emerging Immune Checkpoints
Emerging immune checkpoints represent a new frontier in cancer
immunotherapy, offering novel targets to enhance the body’s immune
response against tumors. While therapies targeting well-known
checkpoints such as PD-1/PD-L1 and CTLA-4 have revolutionized cancer
treatment, many patients still experience resistance or limited efficacy
[2, 5]. To address these challenges, researchers are exploring
additional inhibitory and stimulatory pathways that regulate immune cell
function. Immune checkpoints like TIGIT, LAG-3, VISTA, TIM-3 and others,
are increasingly being recognized for their significance in regulating
immune responses within the tumor microenvironment (TME) [Table 1]
[6]. These emerging targets are drawing attention due to their
potential to influence the effectiveness of cancer immunotherapies by
modulating the immune system’s ability to recognize and attack tumor
cells (Figure 1) [6, 7, 8]. By targeting these novel checkpoints,
either alone or in combination with existing therapies, there is
potential to overcome resistance mechanisms, treat a broader range of
cancers, and ultimately improve patient outcomes.
2.1 TIGIT (T Cell Immunoreceptor with Ig and ITIM
Domains)
TIGIT (T cell immunoreceptor with Ig and ITIM domains) also known as
WUCAM (Washington University Cell Adhesion Molecule), Vstm3 , and VSIG9,
is an inhibitory receptor of the Ig superfamily, found on the surface of
activated CD8+ T and CD4+ T cells, regulatory T cells (Tregs),
follicular T helper cell and natural killer (NK) cells [9, 10].
However, expression of tigit is weak on naïve T cells. TIGIT is a member
of the continually growing family of poliovirus receptor (PVR)-like
proteins [11]. TIGIT is composed of an extracellular immunoglobulin
variable domain, a type I transmembrane domain, and a short
intracellular domain containing one immunoreceptor tyrosine-based
inhibitory motif (ITIM) and one immunoglobulin tyrosine tail (ITT)-like
motif [11, 12]. TIGIT is expressed on natural killer (NK) cells and
T cells, including CD4+ T cells, CD8+ T cells, and regulatory T cells
(Tregs) [13, 14]. While TIGIT expression is typically low in naive
cells, both T cells and NK cells have been shown to upregulate TIGIT
upon activation [12, 13, 14].
Its primary role is to regulate immune responses, maintaining a balance
to prevent over activation that could lead to autoimmunity [13, 14].
TIGIT competes with the co-stimulatory receptor CD226 (DNAM-1) for
binding to the same ligands, primarily CD155 and, to a lesser extent,
CD112 and CD113, which are expressed on antigen-presenting cells (APCs)
including dendritic cells, macrophages [10], and various tumor cells
including melanoma [15], colon cancer [16], pancreatic cancer
[17], lung adenocarcinoma [18], and glioblastoma [19].
When TIGIT binds to CD155 on APCs or tumor cells, it transmits
inhibitory signals to the T cells and NK cells, leading to a suppressed
immune response . This suppression helps tumors evade the immune system,
contributing to tumor growth and progression [9, 10]. The engagement
of TIGIT with CD155 also inhibits the activation and function of CD226
(DNAM-1) in a cell‐intrinsic manner , further dampening immune responses
[20, 21].
Elevated levels of TIGIT have been observed in the cellular
microenvironment of various cancers including melanoma [10],
non‐small‐cell lung carcinoma (NSCLC) [22], colorectal
adenocarcinoma [23], gastric cancer [24], breast cancer
[25], acute myeloid leukaemia (AML) [26] and multiple myeloma
(MM) [27], correlating with an unfavorable prognosis for cancer
patients. Numerous studies have documented increased TIGIT expression on
CD8+ T cells, alongside reports of elevated TIGIT levels on
tumor-infiltrating regulatory T cells (Tregs) and NK cells [28, 29,
30]. Several studies have revealed that high TIGIT expression on
tumor-infiltrating lymphocytes (TILs) correlates with poor clinical
outcomes in cancer [31, 32, 33]. Sun et al showed that, high TIGIT
expression in lung adenocarcinoma was linked to advanced TNM staging,
lymphoid metastasis, distant metastasis, and low expression of antitumor
immunity-related genes [34]. A study by Liu et al revealed that, in
patients with hepatocellular carcinoma, high TIGIT expression in CD8+
T-cell populations in peripheral blood is inversely correlated survival.
[35]. Further in melanoma patients, an elevated TIGIT/CD226 ratio in
Tregs is associated with higher Treg frequencies in tumors and poorer
clinical outcomes [29] . In endometrial cancer, increased levels of
TIGIT on NK cells residing within tumors have been linked to the
severity of the disease [36]. A study by Kong et al., noted that,
TIGIT expression on CD8+ T cells from peripheral
blood collected from patients with AML was increased and was associated
with poor prognosis [26] . However as revealed by Ma et al.,
Increased TIGIT expression in gastric cancer appears to be a positive
indicator. It is associated with an active immune landscape, improved
survival, greater sensitivity to immunotherapy, and a favorable
prognosis. Patients with high TIGIT expression respond better to
immunotherapy compared to those with low TIGIT expression [37].
Preclinical studies have shown that blocking TIGIT can enhance the
activity of T cells and NK cells [27, 30]. This blockade prevents
TIGIT from binding to CD155, thereby allowing CD226 to interact with
CD155 unimpeded. The interaction of CD226 with CD155 provides
stimulatory signals that promote T cell and NK cell activation,
proliferation, and cytotoxic activity against tumor cells. However,
single TIGIT blockade is found to be insufficient in suppressing the
growth of tumors in several experimental tumor models [21, 38,
39].. Several groups have shown that, combining TIGIT blockade with
inhibitors of the PD-1/PD-L1 pathway, another critical immune checkpoint
pathway, shows synergistic effects. Blocking both TIGIT and PD-1/PD-L1
pathways can significantly enhance anti-tumor immunity by unleashing T
cell and NK cell responses, leading to more effective tumor eradication
[39, 40, 41]. Zhang et al, observed that while a single TIGIT
inhibitor only upregulated IFN-γ and TNF-α, the combination of
anti-TIGIT and anti-PD-1 inhibitors significantly upregulated IL-2,
IFN-γ, and TNF-α in CD4+ and CD8+ T cells. This combination could
enhance the anti-leukemia immune response. [42]. In the MC38 model,
the combined blockade of TIGIT and PD-1 resulted in significantly
enhanced effector functions of both CD4+ and CD8+ T cells compared to
blocking either pathway alone. Additionally, this dual blockade achieved
a 100% cure rate [43].
These findings have generated significant interest in the potential
therapeutic use of TIGIT inhibitors in cancer immunotherapy [44,
45]. Clinical trials are ongoing to evaluate the safety and efficacy
of TIGIT blockade, both as monotherapy and in combination with
PD-1/PD-L1 inhibitors, in various types of cancer [NCT04952597,
Ociperlimab (anti-TIGIT antibody) + tislelizumab (PD-1 inhibitor) +
chemoradiotherapy or Tislelizumab + chemoradiotherapy] [NCT04995523,
AZD2936 (bispecific, humanized IgG1 targeting PD-1 and TIGIT)]
[NCT04746924, ociperlimab+ tislelizumab or Pembrolizumab]
[NCT03563716, Tiragolumab (TIGIT inhibitor) + atezolizumab]
[NCT04256421, Tiragolumab + atezolizumab + chemotherapy or
Atezolizumab + chemotherapy] [NCT04294810, Tiragolumab +
atezolizumab or Atezolizumab] [NCT04672356 , IBI939 (anti TIGIT
monoclonal antibody) + sintilimab (PD-1 blocker)]. The results of
these trials, may pave the way for new treatment strategies that improve
the outcomes for patients with cancer by utilizing the power of the
immune system. A recent clinical trial discovered that Elraglusib
(9-ING-41) decreased TIGIT expression on CD8+ T cells, thereby exerting
an inhibitory effect on melanoma [46]. In CITYSCAPE trial (phase 2
study) , patients with chemotherapy-naive, PD-L1-positive, recurrent, or
metastatic non-small cell lung cancer (NSCLC), the combination of
tiragolumab (anti-TIGIT inhibitory immune checkpoint agents) and
atezolizumab (anti-PD-L1) demonstrated a clinically meaningful
improvement in objective response rate and progression-free survival
compared to placebo plus atezolizumab [40].