Human γδ T cells comprise a first line of defense through T-cell receptor (TCR) recognition of stressed cells. However, the molecular determinants and stress pathways involved in this recognition are largely unknown. Here we show that exposure of tumor cells to various stress situations led to tumor cell recognition by a Vγ8Vδ3 TCR. Using a strategy that we previously developed to identify antigenic ligands of γδ TCRs, annexin A2 was identified as the direct ligand of Vγ8Vδ3 TCR, and was found to be expressed on tumor cells upon the stress situations tested in a reactive oxygen species-dependent manner. Moreover, purified annexin A2 was able to stimulate the proliferation of a Vδ2 neg γδ T-cell subset within peripheral blood mononuclear cells and other annexin A2-specific Vδ2 neg γδ T-cell clones could be derived from peripheral blood mononuclear cells. We thus propose membrane exposure of annexin A2 as an oxidative stress signal for some Vδ2 neg γδ T cells that could be involved in an adaptive stress surveillance.gamma-delta T cells | innate-like lymphocytes | cell stress surveillance | tumor immunology | cytomegalovirus
TIGIT is an immune checkpoint inhibitor expressed by effector CD4 + and CD8 + T, NK cells and regulatory T-cells. Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT monoclonal antibodies (mAbs) has shown in vitro potential to restore T-cell functions and therapeutic efficacy in murine tumor models when combined with an anti-PD(L)-1 antibody. Here, we demonstrate for the first time, broader TIGIT expression than previously reported in healthy donors and cancer patients: being observed on T-cells, particularly in CMVseropositive donors and on tumor cells from hematological malignancies such as cutaneous T -cell lymphoma. Quantification of TIGIT density revealed tumor-infiltrating Treg as the population expressing the highest receptor density. Consequently, the therapeutic potential of anti-TIGIT mAbs might be broader than the previously described anti-PD(L)-1 like restoration of T-cell function. In addition to T-cell re-invigoration, CD155 also mediated inhibition in T-cells, an immune population not previously described to be sensitive to TIGIT inhibition, and could be fully prevented via use of an antagonistic anti-TIGIT mAb (EOS884448). In PBMC from cancer patients, as well as TILs from mice, the higher TIGIT expression in Treg correlated with strong antibody-dependent killing and preferential depletion of this highly immunosuppressive population. Accordingly, ADCCenabling anti-TIGIT mAb had superior antitumor activity, that was depending on Fc receptor engagement. In addition, we induced direct killing of TIGIT-expressing tumor cells both in human patient material and animal models, demonstrating strong rational for therapeutic intervention in heme malignancies. These findings reveal broad therapeutic opportunities for anti-TIGIT mAbs in cancer therapeutics.
Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors. Inhibition of PCs in T cells using the general protein-based inhibitor a1-PDX or the pharmacologic inhibitor Decanoyl-Arg-Val-Lys-Arg-chloromethylketone repressed PD-1 and exhausted CTLs via induction of T-cell proliferation and apoptosis inhibition, which improved CTL efficacy against microsatellite instable and microsatellite stable colon cancer cells. In vivo, inhibition of PCs enhanced CTL infiltration in colorectal tumors and increased tumor clearance in syngeneic mice compared with immunodeficient mice. Inhibition of PCs repressed PD-1 expression by blocking proteolytic maturation of the Notch precursor, inhibiting calcium/NFAT and NF-kB signaling, and enhancing ERK activation. These findings define a key role for PCs in regulating PD-1 expression and suggest targeting PCs as an adjunct approach to colorectal tumor immunotherapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.