Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

Abstract

Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for a substantial number of cancer patients. However, the response rates to ICIs vary significantly among individuals and cancer types, with a notable proportion of patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed as a potential strategy to address these challenges. One of the targets is TIGIT, an inhibitory receptor associated with T-cell exhaustion. TIGIT has diverse immunosuppressive effects on the cancer immunity cycle, including the inhibition of natural killer cell effector function, suppression of dendritic cell maturation, promotion of macrophage polarization to the M2 phenotype, and differentiation of T cells to regulatory T cells. Furthermore, TIGIT is linked with PD-1 expression, and it can synergize with PD-1/PD-L1 blockade to enhance tumor rejection. Preclinical studies have demonstrated the potential benefits of co-inhibition of TIGIT and PD-1/PD-L1 in enhancing anti-tumor immunity and improving treatment outcomes in several cancer types. Several clinical trials are underway to evaluate the safety and efficacy of TIGIT and PD-1/PD-L1 co-inhibition in various cancer types, and the results are awaited. This review provides an overview of the mechanisms of TIGIT and PD-1/PD-L1 co-inhibition in anti-tumor treatment, summarizes the latest clinical trials investigating this combination therapy, and discusses its prospects. Overall, co-inhibition of TIGIT and PD-1/PD-L1 represents a promising therapeutic approach for cancer treatment that has the potential to improve the outcomes of cancer patients treated with ICIs.

Keywords: Combined therapy; Immune checkpoint inhibitors; PD-1; PD-L1; TIGIT.

Fig. 1

(A) Direct inhibitory effects of TIGIT. Firstly, TIGIT can directly inhibit the cytotoxic activity of T cells and NK cells by competitively antagonizing the stimulatory action of CD226. CD226 activation occurs upon binding with CD155 or CD112, which activates LFA-1, alters the conformation of ICAM-1, recruits Fyn, and drives the activation of the Akt signaling pathway, leading to the release of IFN-γ. Secondly, TIGIT can bind to CD155, and its ITT-like motif interacts with Grb2, which recruits SHIP1, thereby inhibiting PI3K, MAPK, and NF-κB signaling pathways. In addition, TIGIT also participates in the downregulation of the TCR complex itself and the central regulatory factors of TCR signaling cascades, such as PLCγ. TIGIT can also alter T cell metabolism by inhibiting glycolysis and synergizing with HIF1-α to enhance tumor cell invasion, colony formation, and angiogenesis. (B) Indirect inhibitory effects of TIGIT. Firstly, TIGIT exerts indirect inhibitory effects by triggering CD155 to induce DC acquisition of an immature tolerogenic phenotype, increasing IL-10 secretion, and decreasing IL-12 production. TIGIT can promote naive T cell differentiation into Treg cells more frequently and upregulate Foxp3 expression, which confers superior suppressive function to Treg cells. Finally, activation of the TIGIT/CD155 pathway can promote IL-10 transcription and induce macrophage polarization toward an anti-inflammatory M2 cytokine profile

Fig. 2

Mechanism of co-inhibition by TIGIT and PD-1. The TIGIT/CD226 pathway and the PD-1/PD-L1 pathway have an intersecting crossroad. On the one hand, upon activation by PD-L1, the intracellular domain of PD-1 recruits Shp2 to dephosphorylate CD226, inhibiting the immune activation function of CD226. On the other hand, TIGIT has a higher affinity (dissociation constant 1–3 nM) to CD155 than that of CD226 (dissociation constant 119 nM) [25], thus competitively antagonizes and blocks CD226 homodimerization through its extracellular domain, inhibiting the immune activation function of CD226.