Chapter 2 Fragment Screen of T cell immunoreceptor with Ig and ITIM domains
2.1 Introduction
2.1.2 TIGIT negatively regulates several steps in the cancer immunity cycle
NK cells are thought to be most important in the early stages of cancer elimination and in preventing metastases, but also as cytolytic effector cells as they participate in the release of tumor antigens. TIGIT signaling has been best studied on NK cells where it can signal through its ITIM as an immune-inhibiting receptor.74 Ligation of cognate receptor PVR on target cells results in diminished NK cell effector function.78–80 NK cells from TIGIT-deficient mice produced more interferon gamma (IFN-g) in the presence of PVR-expressing target cells, whereas TIGIT-transgenic NK cells produced less IFN-g than WT cells. TIGIT signaling leads to a strong reduction of NK cytotoxicity, granule
polarization, and cytokine secretion in NK cells.74,79,80 These data suggest that TIGIT- mediated regulation of NK cell function impacts step 1 of the cancer immunity cycle by inhibiting the cytotoxicity of innate immune NK cells (Figure 2-1).
Figure 2-1. TIGIT inhibits the Cancer Immunity Cycle at several steps.
TIGIT can inhibit immune cells at multiple steps in the cancer immunity cycle. Starting with step 1, TIGIT can inhibit NK cell effector function preventing initial tumor cell death and release of cancer cell antigens.
At step 2, TIGIT on T cells can suppress dendritic cell co-stimulatory abilities, leading to reduced cancer antigen presentation and increased anti-inflammatory cytokines such as IL-10. At step 3, TIGIT+ Tregs or PVR-stimulated myeloid cells can suppress CD8+ T cell effector function or skew CD4+ T cell polarization.
At the final step in the cycle, TIGIT can directly inhibit CD8+ T cell effector function, or TIGIT+ Tregs can inhibit CD8+ T cells and prevent the elimination of cancer cells. Adapted from Manieri et al., 2017.81
Cancer cells can evade immune responses as a result of an immunosuppressive tumor microenvironment (TME). TIGIT induces dendritic cells (DCs) to acquire a tolerogenic phenotype via ligation of PVR, resulting in elevated immunosuppressive IL- 10 expression and concomitant reduction in pro-inflammatory IL-12.31 IL-10 is an immunosuppressive cytokine that acts on T cells directly and prevents antigen-presenting cells from upregulating molecules involved in antigen presentation, thereby suppressing T cell proliferation and elaboration of effector cytokines such as IFN-g. TIGIT may also affect cytokine balance by shifting the immune response towards one dominated by IL- 10 by skewing T cell differentiation away from pro-inflammatory Th1 and Th17 phenotypes and towards Th2.34,82,83 These data suggest TIGIT can modulate the TME and its immunosuppressive properties affect step 2 of the cancer immunity cycle because a pro-inflammatory environment is needed to properly activate DCs (Figure 2-1).
Regulatory T cells (Tregs) can influence multiple steps of the cancer immunity cycle, including the suppression of effector T cell activation and cytotoxicity (Figure 2-1).
TIGIT is constitutively expressed by most Tregs and has been shown to play an important role in the function and maintenance of these cells.36,84 TIGIT+ Tregs have been shown to be more immunosuppressive than TIGIT- Tregs by several groups.36,76,84 Furthermore, TIGIT+ Tregs can suppress pro-inflammatory Th1 and Th17 responses but not anti- inflammatory Th2 responses. Tregs may play an important role early in tumor development. However, it remains to be seen if anti-TIGIT therapy, once tumors are established, works by acting on Tregs, CD8+ T cells, or both.
Generating CD8+ T cell antitumor responses is a primary goal for most immunotherapies because it is thought that CD8+ TIL activation is necessary to fully reject
tumors. TIGIT is an important inhibitory molecule found on CD8+ TILs in several different human solid tumors, including lung, colon, breast, uterine, renal, and metastatic melanoma.35 This expression was also found to be tightly associated with PD-1 expression.35,77 TIGIT inhibits productive T cell activation, proliferation, and acquisition of effector functions by targeting molecules in the T cell receptor (TCR) signaling pathway.
When engaged with PVR, TIGIT downregulates components and central regulators of the TCR signaling cascade such as TCR, CD3, and PLC.82 CD8+ TILs expressing high levels of TIGIT are dysfunctional, with reduced capacity for pro-inflammatory cytokine production, higher production of IL-10, and impaired degranulation.76 Interestingly, this dysfunctional state is coupled with the upregulation of anti-apoptotic molecules such as BCL-xL as well as the receptors for cytokines IL-2, IL-7, and IL-15 which promote T cell survival. Therefore, TIGIT inhibits T cell activation but also contributes to the maintenance of the cells ensuring that, although functionally inactivated, they are retained for future activation.
Several anti-TIGIT studies have highlighted TIGIT’s inhibitory role on CD8+ T cells in different cancer models. Combined antibody blockade of TIGIT and PD-L1 in mice led to the rejection of CT26 tumors and an increase in IFN-g+ CD8+ T cells in tumors compared to either treatment alone. Anti-TIGIT and anti-PD-1 co-blockade was also able to increase the proliferation and cytokine production of CD8+ TILs from patients with melanoma, and knockdown of TIGIT was able to restore cytokine production by CD8+ T cells from AML patients.77,85 Furthermore, TIGIT–PVR interactions controlled melanoma- specific T cell responses during the effector phase.86 High expression of TIGIT was found on melanoma TILs, whereas CD226 was downregulated, suggesting that there may be a
tipping point at which the inhibitory signal of TIGIT can overcome the activation signal of CD226. PVR expression levels on tumor cells also contributed to the strength of TIL responses. Collectively, these data suggest that TIGIT can modulate CD8+ T cell effector function and effect the final stage in the cancer immunity cycle (Figure 2-1).