Correction to: Increased TIGIT expressing NK cells with dysfunctional phenotype in AML patients correlated with poor prognosis
Guanfang LiuQi ZhangJingying YangXiaomin LiLuhua XianWenmin LiTing LinJuan ChengQiwen LinXiuzhang XuQin LiLin YuMaohua ZhouErxia Shen
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TIGIT
Dysfunctional family
This study aims to explore whether TIGIT is an effective target for the immunotherapy of renal cell cancer (RCC) with PD‐1 as a positive control. The expression of TIGIT and PD‐1 in RCC and peripheral blood mononuclear cells (PBMC) and the correlation between TIGIT and PD‐1 are evaluated. The expression of TIGIT and PD‐1 is inhibited, and then the proliferation, apoptosis, and migration are assessed. TIGIT expression is positively related to the expression of PDCD1, BTLA, ICOS, and FOXP3 ( p < 0.05). TIGIT expression in the PBMC, TIL, RCC, and adjacent normal tissues is higher than PD‐1 expression. Blocking the TIGIT and PD‐1 signaling pathways significantly inhibits the proliferation, migration, and invasion of RCC cells and promotes their apoptosis. These effects are more evident in TIGIT inhibitors than in PD‐1 inhibitors. TIGIT inhibitor mainly regulates the expression of differential genes to achieve the reconstruction of immune killing and restore the killing effect on the RCC, and its mechanism by which TIGIT functions overlap that of PD‐1 inhibitor. TIGIT may become a target for the immunotherapy of RCC, and there is a theoretical basis for the combination of TIGIT inhibitors and PD‐1 inhibitors for the treatment of RCC.
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Cancer Immunotherapy
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Abstract HIV-specific CD8 + T cells demonstrate an exhausted phenotype associated with increased expression of inhibitory receptors, decreased functional capacity, and a skewed transcriptional profile, which are only partially restored by antiretroviral treatment (ART). Expression levels of the inhibitory receptor, T cell immunoglobulin and ITIM domain (TIGIT), the co-stimulatory receptor CD226 and their ligand PVR are altered in viral infections and cancer. However, the extent to which the TIGIT/CD226/PVR-axis is affected by HIV-infection has not been characterized. Here, we report that TIGIT expression increased over time despite early initiation of ART. HIV-specific CD8 + T cells were almost exclusively TIGIT + , had an inverse expression of the transcription factors T-bet and Eomes and co-expressed PD-1, CD160 and 2B4. HIV-specific TIGIT hi cells were negatively correlated with polyfunctionality and displayed a diminished expression of CD226. Furthermore, expression of PVR was increased on CD4 + T cells, especially T follicular helper (Tfh) cells, in HIV-infected lymph nodes. These results depict a skewing of the TIGIT/CD226 axis from CD226 co-stimulation towards TIGIT-mediated inhibition of CD8 + T cells, despite early ART. These findings highlight the importance of the TIGIT/CD226/PVR axis as an immune checkpoint barrier that could hinder future “cure” strategies requiring potent HIV-specific CD8 + T cells.
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Immune checkpoint
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Abstract Background: TIGIT (T-cell immunoglobulin and ITIM domain), which is primarily expressed on activated and 'exhausted' T and NK cells, is one of the promising 'next generation' immune checkpoint molecules. Engagement of TIGIT to its ligands (i.e., PVR and PVRL2) leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. Anti-TIGIT monoclonal antibodies have shown clinical benefit when combined with anti-PD-L1 agents in NSCLC. However, the single-agent efficacy of anti-TIGIT therapies have been limited. PVRIG (PVR-related immunoglobulin domain containing), which is another coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family, binds with high affinity to PVRL2 and suppresses T-cell function, and shows nonredundant inhibitory effects alongside the TIGIT/PVR/PVRL2 axis. Here, we report a fully-human anti-TIGIT × PVRIG bispecific antibody (anti-TIGIT × PVRIG biAb), which blocks both the PVRIG/PVRL2 and TIGIT/PVR/PVRL2 pathways, that maintains the efficacy of the combination of the two mono-agents. The anti-TIGIT × PVRIG biAb is also highly efficacious when combined with PD1/PD-L1 inhibitors in mouse tumor models. Methods: An anti-TIGIT × PVRIG biAb was generated through the fusing of a fully-human IgG targeting TIGIT with a wild type G1-Fc to a fully-human scFv at the c-terminus targeting PVRIG. Binding affinity and specificity analyses were studied by flow cytometry and biolayer interferometry. The co-binding of the anti-TIGIT × PVRIG biAb to TIGIT and PVRIG was detected by ELISA. The immunomodulatory functions of the anti-TIGIT × PVRIG biAb were evaluated using a luciferase reporter cell assay in vitro and human PBMC-based tumor models in vivo. Results: The anti-TIGIT × PVRIG biAb binds with high affinity to the extracellular domain of human TIGIT/PVRIG and can bind to TIGIT and PVRIG simultaneously. In a competition assay, the anti-TIGIT × PVRIG biAb efficiently blocked the interaction between TIGIT and PVR/PVRRL2, and PVRIG with PVRL2. In a luciferase reporter cell system, the anti-TIGIT × PVRIG biAb induced high levels of luciferase activity compared with the anti-TIGIT or anti-PVRIG mAbs alone. In vivo, the anti-TIGIT × PVRIG biAb demonstrated stronger anti-tumor efficacy than the anti-TIGIT and anti-PVRIG mAbs as monotherapies or combined with anti-PD-1 mAb. Conclusion: Our anti-TIGIT × PVRIG biAb, a fully human bispecific antibody, either alone or in combination with anti-PD-1 mAb promotes immune cell activation both in vitro and in vivo, supporting its clinical development for the treatment of human cancers. The molecule is currently under GLP-toxicity evaluation in NHP, and a first-in-human study is expected to begin in 2022. Citation Format: Shuang Dai, Weifeng Huang, Zhijun Yuan, Shaogang Peng, Jiayi Si, Chao Wang, Xiaoniu Miao, Yingda Xu, Joanne Sun, Xiaolin Liu, Andy Tsun, Tianhang Zhai. A novel fully human anti-TIGIT and PVRIG bispecific antibody that elicits potent anti-tumor efficacy in pre-clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5527.
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Abstract The generation of blocking antibodies against co-inhibitory receptors involved in T cell exhaustion is a recent key strategy for cancer immunotherapy. We have shown that co-blockade of TIGIT and PD-L1 results in tumor rejection by restoring the function of exhausted tumor-infiltrating CD8+ T cells. We were then interesting in deciphering the molecular mechanism of action of this anti-TIGIT blocking antibody. We hypothesized that TIGIT might inhibit a complementary co-activating receptor. Interestingly, TIGIT expression on tumor infiltrating CD8+ T cell was correlated with CD226, which binds a common receptor PVR. To better understand the relationship between these co-receptors, we utilized Time-resolved Fluorescence Resonance Energy (TR-FRET), a technology that allows for monitoring of cell surface protein interactions in real time. We showed that CD226 forms homodimers, and that co-expression of CD226 with TIGIT results in 1) the attenuation of CD226 self-association and 2) the formation of a TIGIT/CD226 complex in cis. Strikingly, anti-TIGIT antibody causes a significant decrease of the TIGIT/CD226 interaction. These observations indicate that the interaction of CD226 and TIGIT may play a central role in the antitumor effects of anti-TIGIT. Indeed, anti-CD226 antibodies blocked the ability of anti-PD-L1/anti-TIGIT to inhibit tumor growth in mice. Altogether, these results depict a close relationship between TIGIT and CD226 in CD8+ mediated T cell exhaustion.
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Human NK cells display extensive phenotypic and functional heterogeneity among healthy individuals, but the mechanism responsible for this variation is still largely unknown. Here, we show that a novel immune receptor, T-cell immunoglobulin and ITIM domain (TIGIT), is expressed preferentially on human NK cells but shows wide variation in its expression levels among healthy individuals. We found that the TIGIT expression level is related to the phenotypic and functional heterogeneity of NK cells, and that NK cells from healthy individuals can be divided into three categories according to TIGIT expression. NK cells with low levels of TIGIT expression show higher cytokine secretion capability, degranulation activity, and cytotoxic potential than NK cells with high levels of TIGIT expression. Blockade of the TIGIT pathway significantly increased NK-cell function, particularly in NK cells with high levels of TIGIT expression. We further observed that the TIGIT expression level was inversely correlated with the IFN-γ secretion capability of NK cells in patients with cancers and autoimmune diseases. Importantly, we propose a novel mechanism that links TIGIT expression with NK-cell functional heterogeneity, and this mechanism might partially explain why individuals have different susceptibilities to infection, autoimmune disease, and cancer.
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The T-cell immunoglobulin and ITIM domain (TIGIT) is a new inhibitory receptor that represents a novel target for the development of immunotherapy strategies. Using an in-silico approach, we identified differentially expressed genes (DEGs) and enriched pathways associated with TIGIT mRNA expression, in high grade serous ovarian cancer (HGSOC) using the Cancer Genome Atlas (TCGA) and the Australian Ovarian Cancer Study (AOCS).
Methods
DEGs between patients with high and low TIGIT expression, stratified based on an unsupervised tree analysis were calculated using EdgeR. Enriched pathways with the DEG list were identified using Gene Set Enrichment Analysis (GSEA) using a False Discovery Rate (FDR) <0.25 as significant.Results
Increased TIGIT mRNA expression was associated with improved survival in HGSOC (p=0.034). 975 DEGs were identified in the TIGIT high group, and GSEA identified enriched pathways involved in complement activation humoral immune response, suggesting that TIGIT expression may be associated with an immunologically 'hot' tumour. This was confirmed by the finding that increased TIGIT expression was associated with an increased lymphocytic infiltration score, CD8+ T cells and Interferon Gamma Response score. Finally TIGIT expression was reduced in AOCS samples from women with acquired platinum resistance compared to matched primary tumour samples (p=0.014)Conclusion
TIGIT represents an important prognostic marker in HGSOC. Similar to PD-1/PD-L1, TIGIT is associated with increased tumour infiltrating lymphocytes and an improved prognosis. Platinum resistance is associated with a reduction in TIGIT expression and warrants further study in HGSOC.TIGIT
Immune checkpoint
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Background
Recently, TIGIT+PD1 blockade was shown to confer additive survival benefits in orthotopic glioblastoma and colon cancer mouse models1 2—notably, this included experiments3 that used the 1G9 TIGIT monoclonal antibody (mAb) that has potentially agonistic effects.1 Herein we investigated the TIGIT/CD226/CD155 axis and effects of combining clinically analogous PD-1/PD-L1 mAbs with TIGIT-targeting 1G9 mAb in murine glioblastoma models.Methods
The overall survival (OS) associated with TIGIT (non-depleting IG9; 200μg every 3days for 4 doses),1 PD-1 (8H3; initial 500μg followed by 250μg every 3days for 7 doses), PD-L1 (6A2; initial 500μg followed by 250μg every 3days for 7 doses), and/or IgG mAbs was assessed in immunocompetent C57BL/6 albino mice intracranially implanted with syngeneic GL261-luc2 or CT2A-luc.4 5 The roles of T cells and NK cells were examined using depletion with CD8a, CD4, or NK1.1 mAbs. Expression of TIGIT/CD226/CD155 and PD-1/PD-L1/PD-L2 by tumor and tumor-infiltrating immune cells was evaluated using flow cytometry and RT-qPCR.Results
In vitro, GL261-luc2 and CT2A-luc tumor cells moderately expressed PD-L1, PD-1, and TIGIT; but strongly expressed TIGIT's inhibitory ligand CD155.(Figure1A-B) Ex vivo, >83% of CD8+ and CD4+TILs in GL261-luc2 co-expressed TIGIT+/CD226+: ≥2x the proportions in CT2A-luc.(Figure 2A) CD155 and PD-L1 were highly co-expressed on tumor-infiltrating macrophages: greater in GL261-luc2 than CT2A-luc tumors.(Figure 2B)In GL261-luc2 mice, anti-TIGIT monotherapy displayed minimal OS improvement; whereas anti-PD-1 and anti-PD-L1 monotherapies demonstrated robust OS responses.(Figure 3A) Adding anti-TIGIT to PD-1/PD-L1 blockade demonstrated synergism with anti-PD-1. Anti-TIGIT plus anti-PD-1 displayed nominally improved OS in CT2A-luc compared to anti-PD-1 monotherapy (p=0.11).(Figure 3B).Given robust T-cell expression of TIGIT and PD-1, we examined how CD4+ or CD8+ depletion affected responses in GL261-luc2 mice: depletion completely abrogated anti-PD-1's benefits.(Figure 4) Although CD4/CD8 depletion also reduced anti-TIGIT+anti-PD1's efficacy, the resulting OS matched that of non-depleted anti-PD-1 monotherapy. Additionally, NK cell depletion had no effect on anti-TIGIT+anti-PD1's efficacy.Conclusions
Our results recapitulate published findings regarding the synergistic benefits of combining TIGIT 1G9 mAb with anti-PD-1 using the clinically-relevant 8H3 mAb in syngeneic mouse glioblastoma, and extend those findings to anti-TIGIT+anti-PDL1 combinations. TIGIT/CD226 was highly co-expressed by immuno-responsive GL261-luc2's tumor-infiltrating lymphocytes (TILs); wheres CD155/PD-L1 expression predominated in tumor-infiltrating myeloid cells. Depletion of CD8+ or CD4+ TILs modestly reduced anti-TIGIT+anti-PD1's efficacy—suggesting a mechanism that is at least partially independent of T (and NK) cells. Our preliminary results suggest a complex interplay between TIGIT/CD226/CD155 and PD-1/PD-L1/PD-L2 axes in tumors and their microenvironmental constituents that warrants further investigation; plus, careful consideration of antibody clones' functionality is necessary for designing immunotherapy combinations.Acknowledgements
We gratefully acknowledge the support of the The Jennifer Oppenheimer Cancer Research Initiative; The Ben and Catherine Ivy Foundation; Hope It's A Beach Thing; and the Pan Mass Challenge (Erica's Entourage and CRUS11TOUR), and the NCI (P01CA236749; K12CA090354).References
Dixon KO, Schorer M, Nevin J, Etminan Y, Amoozgar Z, Kondo T, Kurtulus S, Kassam N, Sobel RA, Fukumura D, Jain RK, Anderson AC, Kuchroo VK, Joller N. Functional anti-TIGIT antibodies regulate development of autoimmunity and antitumor immunity. J Immunol 2018 April 15;200(8):3000–3007. Hung AL, Maxwell R, Theodros D, Belcaid Z, Mathios D, Luksik AS, Kim E, Wu A, Xia Y, Garzon-Muvdi T, Jackson C, Ye X, Tyler B, Selby M, Korman A, Barnhart B, Park SM, Youn JI, Chowdhury T, Park CK, Brem H, Pardoll DM, Lim M. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. Oncoimmunology 2018 May 24;7(8):e1466769. Raphael I, Kumar R, McCarl LH, Shoger K, Wang L, Sandlesh P, Sneiderman CT, Allen J, Zhai S, Campagna ML, Foster A, Bruno TC, Agnihotri S, Hu B, Castro BA, Lieberman FS, Broniscer A, Diaz AA, Amankulor NM, Rajasundaram D, Pollack IF, Kohanbash G. TIGIT and PD-1 immune checkpoint pathways are associated with patient outcome and anti-tumor immunity in glioblastoma. Front Immunol 2021 May 7;12:637146. Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, Jones KL, Conway AS, Liao X, Zhou J, Wen PY, Van Den Abbeele AD, Hodi FS, Qin L, Kohl NE, Sharpe AH, Dranoff G, Freeman GJ. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res 2016 February;4(2):124–35. Iorgulescu JB, Gokhale PC, Speranza MC, Eschle BK, Poitras MJ, Wilkens MK, Soroko KM, Chhoeu C, Knott A, Gao Y, Lim-Fat MJ, Baker GJ, Bonal DM, Nguyen QD, Grant GRL, Ligon KL, Sorger PK, Chiocca EA, Anderson AC, Kirschmeier PT, Sharpe AH, Freeman GJ, Reardon DA. Concurrent dexamethasone limits the clinical benefit of immune checkpoint blockade in glioblastoma. Clin Cancer Res 2021 January 1;27(1):276–287.TIGIT
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Abstract Immune checkpoint blockade targeting PD-1/PD-L1 has enjoyed tremendous success in the clinic against various advanced stage cancers, unleashing potent and durable immune-mediated control of tumors while vastly improving patient survival. However, only a portion of patients truly benefit, while other cancers, such as breast, prostate, pancreatic, and colon cancers, are largely resistant to PD-1/PD-L1 therapy alone. Targeting additional immunosuppressive proteins could boost the efficacy of anti-PD-1/PD-L1 therapy and bring the benefits of immunotherapy to more patients. TIGIT is a recently identified immune checkpoint protein mainly expressed by T and NK cells. CD155 (PVR) is a high-affinity receptor of TIGIT, while CD112 and CD113 bind it with weaker affinity. CD155 and CD112 can engage CD226, an NK activating receptor also expressed on some CD8+ T cells, and trigger killing of tumors. Competitive binding of TIGIT to CD155 and CD112 would prevent signaling through CD226. Therefore, anti-TIGIT blocking antibodies may enhance the function of NK cells and T cells. Preclinical studies have shown that inhibition of TIGIT promotes proliferation and function of T cells. Combined blockade of both TIGIT and PD1/PD-L1 has also shown superior efficacy over monotherapy against tumors in early phase clinical trials. Given the intensive interest in combined TIGIT and PD-1/PD-L1 therapies for cancer, Biocytogen has established a novel human PD-1/PD-L1/TIGIT triple knock-in (TKI) mouse as a vital tool to pre-clinically evaluate the in vivo efficacy of combined human TIGIT and PD1/PD-L1 blocking agents against tumors compared to either alone. Exon 2 of the mouse PD-1 gene, exon 3 of mouse PD-L1, and exon 2 of mouse TIGIT were replaced by their human homologs in B-hPD-1/hPD-L1/hTIGIT mice. Human PD-1, PD-L1, and TIGIT proteins were expressed in homozygous B-hPD-1/hPD-L1/hTIGIT but not wildtype mice. Immune profiles of B-hPD-1/hPD-L1/hTIGIT mice were similar to those in wild-type C57BL/6 mice, and abnormalities were not observed. Importantly, we showed that combining anti-human PD-L1 and anti-human TIGIT antibodies significantly inhibited the growth of MC38-hPD-L1 tumor cells implanted into B-hPD-1/hPD-L1/hTIGIT mice. Thus, our novel hPD-1/hPD-L1/hTIGIT TKI mice will be very useful for investigating the in vivo efficacy of TIGIT antibodies currently in company pipelines both alone and combined with PD1/PD-L1 antibody drugs. Citation Format: Chonghui Liu, Xiaofei Zhou, Yanan Guo, Eugene Lin, Luke (Zhaoxue) Yu, Yuelei Shen. A novel humanized B-hPD-1/hPD-L1/hTIGIT mouse model reveals enhanced efficacy of combined TIGIT and PD-L1 blockade against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 493.
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Natural killer (NK) cells are important for maintenance of innate immune system stability and serve as a first line of defense against tumors and virus infections; they can act either directly or indirectly and are regulated via co-operation between inhibitory and stimulatory surface receptors. The recently reported inhibitory receptor, TIGIT, can be expressed on the NK cell surface; however, the expression level and function of TIGIT on NK cells during HIV infection is unknown. In this study, for the first time, we investigated the expression and function of TIGIT in NK cells from HIV-infected individuals. Our data demonstrate that the level of TIGIT is higher on NK cells from patients infected with human immunodeficiency virus (HIV) compared with HIV-negative healthy controls. TIGIT expression is inversely correlated with CD4+ T cell counts and positively correlated with plasma viral loads. Additionally, levels of the TIGIT ligand, CD155, were higher on CD4+ T cells from HIV-infected individuals compared with those from healthy controls; however, there was no difference in the level of the activating receptor, CD226, which recognizes the same ligands as TIGIT. Furthermore, TIGIT was found to specifically up-regulated on CD226+ NK cells in HIV-infected individuals, and either rIL-10, or rIL-12 + rIL-15, could induce TIGIT expression on these cells. In addition, high TIGIT expression inhibited the production of interferon-gamma (IFN-γ) by NK cells, while TIGIT inhibition restored IFN-γ production. Overall, these results highlight the important role of TIGIT in NK cell function and suggest a potential new avenue for the development of therapeutic strategies toward a functional cure for HIV.
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