Abstract
TIGIT, an immune checkpoint molecule widely expressed on NK cells, activated T cells and Tregs, has been involved in delivering inhibitory signals through the interaction with PVR. The blockade of TIGIT/PVR interaction is a promising approach in cancer immunotherapy. Here, we unexpectedly discovered the expression of TIGIT in murine tumor cells. To elucidate the mechanism of such intrinsic expression, TIGIT knockout murine colorectal CT26 and MC38 cell lines were generated by using CRISPR/Cas9 system. Although TIGIT knockout showed no effects on proliferation and colony formation of tumor cells in vitro, the tumor growth in mice was considerably inhibited. TIGIT knockout led to the increase of IFN-γ secretion by NK and CD8+ T cells. Further, in BABL/c nude mice, CD8+ T cells depleting mice and NK cells depleting nude mice, the promotion of tumor growth was significantly diminished, suggesting that both NK cells and CD8+ T cells were involved in the tumor promoting process mediated by intrinsic TIGIT. In addition, blocking TIGIT/PVR interaction by the antibody or recombinant PVR protein could elicit anti-tumor effects by facilitating the tumor infiltration and restoring the function of CD8+ T cells, and the antibody-mediate TIGIT blockade could inhibit MC38 tumor growth through blocking TIGIT expressed on tumor cells. We therefore propose a novel TIGIT/PVR interaction mode that tumor intrinsic TIGIT delivers inhibitory signals to CD8+ T cells and NK cells by engaging with PVR.
Highlights
More and more work from both clinical and basic research revealed that immune checkpoint blockade, especially CTLA-4 and PD-1/PD-L1, could successfully reinvigorate T cell function to fight against cancer [1,2,3,4,5,6]
We examined TIGIT and PD-1 expression in fresh tumor samples from patients with colorectal cancer, and noticed that TIGIT was highly expressed on CD45+ cells in colorectal cancer samples (Figure 1B, left panel, tumor vs. peri-tumor, p < 0.01)
Among the alternative immune checkpoint molecules, TIGIT is reported to be a promising target for cancer immunotherapy, but its function remains largely unknown[41]
Summary
More and more work from both clinical and basic research revealed that immune checkpoint blockade, especially CTLA-4 and PD-1/PD-L1, could successfully reinvigorate T cell function to fight against cancer [1,2,3,4,5,6]. Antibodies targeting PD-1 or PD-L1 have exhibited persistent clinical benefits with the response rates of approximately 30–40% in patients with advanced cancers [7,8,9]. PD-1 or PD-L1 blockade led to very limited response rate in colorectal cancer patients, only those with microsatellite instability (MSI) might get clinical benefits [16,17,18]. Ligation of PVR with TIGIT mediates inhibitory signals to T cells, but transmits stimulatory signals while binds to CD226 [23]. Recent studies revealed that TIGIT/PVR signaling had been implicated in inhibiting the metabolism of CD8+ T cells, and suppressing the effector function [26]
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