A TIGIT-based chimeric co-stimulatory switch receptor improves T-cell anti-tumor function

Abstract

BackgroundTumors can employ different mechanisms to evade immune surveillance and function. Overexpression of co-inhibitory ligands that bind to checkpoint molecules on the surface of T-cells can greatly impair the function of latter. TIGIT (T cell immunoreceptor with Ig and ITIM domains) is such a co-inhibitory receptor expressed by T and NK cells which, upon binding to its ligand (e.g., CD155), can diminish cytokine production and effector function. Additionally, the absence of positive co-stimulation at the tumor site can further dampen T-cell response.MethodsAs T-cell genetic engineering has become clinically-relevant in the recent years, we devised herein a strategy aimed at enhancing T-cell anti-tumor function by diverting T-cell coinhibitory signals into positive ones using a chimeric costimulatory switch receptor (CSR) composed of the TIGIT exodomain fused to the signaling domain of CD28.ResultsAfter selecting an optimized TIGIT-28 CSR, we co-transduced it along with tumor-specific TCR or CAR into human T-cells. TIGIT-28-equipped T-cells exhibited enhanced cytokine secretion and upregulation of activation markers upon co-culture with tumor cells. TIGIT-28 enhancing capability was also demonstrated in an original in vitro model of T-cell of hypofunction induction upon repetitive antigen exposure. Finally, we tested the function of this molecule in the context of a xenograft model of established human melanoma tumors and showed that TIGIT-28-engineered human T-cells demonstrated superior anti-tumor function.ConclusionOverall, we propose that TIGIT-based CSR can substantially enhance T-cell function and thus contribute to the improvement of engineered T cell-based immunotherapy.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0721-y) contains supplementary material, which is available to authorized users.

TIGIT as an emerging immune checkpoint

“…Other promising combination targets for TIGIT include TIM‐3 , CD112R or CD96 . Interestingly, while most efforts are focused on blocking TIGIT inhibitory activity through mAbs, a recent study considered TIGIT in the context of T cell engineering . Hoogi et al .…”

Targeting glycosylated antigens on cancer cells using siglec‐7/9‐based CAR T‐cells

“…Freshly isolated human PBLs were stimulated for 48 hours in the presence of 50 ng/mL OKT3 (eBioscience, San Diego, CA) before transduction. Following stimulation, lymphocytes were transduced with retroviral vectors by transfer to nontreated tissue culture dishes (Nunc, Rochester, NY,) that had been precoated with RetroNectin (Takara, Japan) and retroviral vectors as previously described 32 …”

Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer

“…Moreover PVR-related Ig domain, (PVRIG) binds CD112, leading to inhibitory signalling. These DNAM-1-competing receptors (TIGIT in particular) have higher affinity for PVRs and consequently have also been proposed as targets for immune checkpoint inhibition [133][134][135]. DNAM-1 has further been shown to synergize with other activating NK cell receptors, promoting cellular activation through an ITT-like motif, and inducing effector cytokine production [136][137][138].…”

“…One potential solution entails the use of a PVR-targeting ligand to direct the specificity of a co-stimulatory switch receptor (CSR). Illustrating this, a TIGIT-based CSR was expressed in human T cells and delivered co-stimulation through a coupled CD28 endodomain, even in the presence of the immunosuppressive cytokine, TGF-β [135]. T cells expressing TIGIT-28 also significantly reduced tumour burden and lengthened survival in a melanoma xenograft model [135].…”