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TIGIT-Fc Promotes Antitumour Immunity

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TIGIT-Fc Promotes Antitumour Immunity bioRxiv preprint doi: https://doi.org/10.1101/2020.10.19.346437; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 TIGIT-Fc Promotes Antitumour Immunity 2 Wenyan Fu1,2, Changhai Lei1, Jian Zhao3 and Shi Hu1, * 3 4 1 Department of Biophysics, College of Basic Medical Sciences, Second Military Medical 5 University, Shanghai 200433, China. 6 2 Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong 7 University School of Medicine, Shanghai 200011, China. 8 3 KOCHKOR Biotech, Inc., Shanghai 202152, China 9 10 *Corresponding Author: Shi Hu, Second Military Medical University, 800 Xiangyin Road, 11 Shanghai, China, 200433. Phone: +86-02181870925. E-mail: [email protected]. 12 13 14 Keywords: Cancer Immunotherapy, TIGIT, Fc fusion, NK cell, T cell 15 16 17 18 19 ~ 1 ~ bioRxiv preprint doi: https://doi.org/10.1101/2020.10.19.346437; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 20 Abstract 21 T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a checkpoint receptor that 22 mediates both T cell and natural killer (NK) cell exhaustion in tumours. An Fc-TIGIT 23 fusion protein was shown to induce an immune-tolerance effect in a previous report, but 24 the relevance of the TIGIT-Fc protein to tumour immunity is unknown. Here, we 25 unexpectedly found that TIGIT-Fc promotes rather than suppresses tumour immunity. 26 TIGIT-Fc treatment promoted the effector function of CD8+ T and NK cells in several 27 tumour-bearing mouse models. Additionally, TIGIT-Fc treatment resulted in potent T cell 28 and NK-cell-mediated tumour reactivity, sustained memory-induced immunity in tumour 29 re-challenge models, enhanced therapeutic effects via an antibody against PD-L1, and 30 induction of Th1 development in CD4+ T cells. TIGIT-Fc showed a potent 31 antibody-dependent cell-mediated cytotoxicity (ADCC) effect but no intrinsic effect on 32 tumour cell development. Our findings elucidate the unexpected role of TIGIT-Fc in 33 tumour immune reprogramming, suggesting that TIGIT-Fc treatment alone or in 34 combination with other checkpoint receptor blockers is a promising anticancer 35 therapeutic strategy. 36 37 38 39 40 41 42 43 44 45 ~ 2 ~ bioRxiv preprint doi: https://doi.org/10.1101/2020.10.19.346437; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 46 Introduction 47 T cell immunoreceptor with Ig and ITIM domains (TIGIT, also known as WUCAM, 48 Vstm3 or VSIG9), which is an inhibitory receptor expressed on lymphocytes belonging to 49 the receptor of the Ig superfamily regulatory network that involves multiple players (e.g., 50 CD96/TACTILE, CD112R/PVRIG), is a major emerging target for cancer 51 immunotherapy1. As an inhibitor of antitumour responses, TIGIT has the capacity to 52 hinder multiple steps of the cancer immunity cycle, and therefore it is of interest in the 53 development of a first-in-class checkpoint-blocking drug2; in addition, new clinical data 54 has shown that combination therapy with the anti-TIGIT antibody tiragolumab combined 55 with atezolizumab appears safe and effective against non-small cell lung cancer 56 (NSCLC)3. Several mechanisms of action have been proposed for TIGIT-mediated 57 inhibition of effector T cells and NK cells and the suppression of tumour-specific 58 immunity. TIGIT was reported to interfere with the co-stimulation effect of DNAM-14 or 59 to directly deliver inhibitory signals to the effector cells5. Additionally, TIGIT was 60 reported to enhance the suppressive functions of regulatory T cell (Tregs) and hence have 61 the potential to inhibit a wide range of immune cells6,7. 62 TIGIT-Fc is an Fc fusion protein in which the extracellular domain of TIGIT is fused 63 genetically to the immunoglobulin Fc domain. This genetic method enables Fc fusion 64 proteins to have some antibody-like properties, such as long serum half-life and easy 65 expression and purification, making them an attractive platform for research agents and 66 therapeutic drugs8. In a previous report, TIGIT-Fc showed an immunosuppressive effect 67 by inhibiting T cell activation in vitro in a dendritic cell-dependent manner and inhibited 68 delayed-type hypersensitivity reactions in mice9. We previously also showed that 69 TIGIT-Fc demonstrates a therapeutic effect in a mouse model of lupus10. Interestingly, 70 TIGIT-Fc was also shown to promote NK cell activation11 and had no effect on cytokine 71 production by tumour-specific CD8+ T cells in vitro12, indicating that TIGIT-Fc may be a 72 multifaceted immunomodulator and that its function may be dependent on the immune 73 microenvironment. In particular, the impact of TIGIT-Fc on antitumour immunity is 74 currently unknown. 75 Here, we unexpectedly found that TIGIT-Fc notably reduced the growth of human ~ 3 ~ bioRxiv preprint doi: https://doi.org/10.1101/2020.10.19.346437; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 76 tumours in a xenograft model containing coimplanted human T cells by supporting a 77 stimulatory immunological mechanism of action for TIGIT-Fc. TIGIT-Fc treatment alone 78 was sufficient to delay tumour growth in vivo and reverse the exhaustion of antitumour T 79 cells and NK cells in multiple tumour models. We further demonstrated that TIGIT-Fc not 80 only directly subverted the exhaustion of tumour-infiltrating NK cells, similar to the 81 effect of blockade of TIGIT with antibodies, but also sustained tumour-specific T cell 82 function in a CD4+ T cell-dependent manner. Moreover, a synergistic effect was achieved 83 by the combined therapy of TIGIT-Fc and PD-L1 blockade. TIGIT-Fc also potentially 84 mediated the ADCC lysis of tumour cells in vitro. Hence, these findings demonstrate that 85 TIGIT-Fc may coordinate both the reversal of NK cell exhaustion and the acceleration of 86 the activation of T cells for tumour control and support the clinical development of 87 TIGIT-Fc for cancer immunotherapy. 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 ~ 4 ~ bioRxiv preprint doi: https://doi.org/10.1101/2020.10.19.346437; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 104 Results 105 TIGIT-Fc unexpectedly shows antitumour immunity 106 Targeting co-inhibitory receptors is highly relevant in cancer where therapeutic 107 effects are being exploited clinically. PD-1/PD-L1 blockers are efficacious in the 108 treatment of cancer, but resistance to this therapy is increasing, and the responses to 109 anti-PD-1 or anti-CTLA-4 immunotherapy are relatively minimal in some tumours (such 110 as colorectal carcinomas). Recent reports have shown that anti-TIGIT antibodies have 111 synergistic effects with PD-1 blockade in cancer, both in pre-clinical and clinical studies. 112 As we and others previously have shown that TIGIT-Fc is an immune-suppressive 113 agents9,10, we initially aimed to test whether TIGIT-Fc has the capacity to promote 114 resistance to anti-PD-L1 therapy in xenograft models of the human melanoma cell line 115 A375. Both TIGIT-Fc and atezolizumab were confirmed to bind to A375 cells (Fig. 1a). 116 To generate allogenic T cell lines with specificity to A375 cells13, primary human T cells 117 were expanded in culture and implanted subcutaneously in NSG mice together with 118 tumour cells. Our data shows that the administration of the anti-PD-L1 antibody 119 atezolizumab led to a notable growth inhibition of the A375 tumour in the presence of 120 human T cells, consistent with a previous report13. Unexpectedly, TIGIT-Fc alone 121 significantly inhibited the tumour growth of A375 xenografts compared with an 122 isotype-matched control antibody. Moreover, the combined therapy of TIGIT-Fc and 123 atezolizumab therapy showed a superior tumour growth inhibition reaching nearly 100% 124 (Fig. 1b). Based on the immunoglobulin-like structure of TIGIT-Fc, we hypothesize that 125 TIGIT-Fc may have a two-sided biological effect in that it is a potent agonist of CD155 126 and a membrane-bound TIGIT antagonist. We tested the antitumour effect of the 127 anti-TIGIT antibody etigilimab in the T cell-based A375 tumour model, but etigilimab 128 alone showed no inhibitory effect on the growth of the A375 tumour xenograft, and 129 combined therapy with etigilimab and atezolizumab showed no synergistic effect 130 compared with atezolizumab monotherapy (Fig. 1c), suggesting that the antitumour 131 efficacy of TIGIT-Fc is not due to TIGIT blockade in A375 xenografts. 132 TIGIT-Fc enhances effector NK cell function in tumour-bearing mice 133 A previous report showed that blockade of TIGIT prevents NK cell exhaustion14. To ~ 5 ~ bioRxiv preprint doi: https://doi.org/10.1101/2020.10.19.346437; this version posted October 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 134 assess whether TIGIT-Fc can blockade TIGIT on NK cells similar to that of an 135 anti-TIGIT antibody in tumour-bearing mice, murine TIGIT-Fc (mTIGIT-Fc) was first 136 tested against subcutaneous MC38 colon adenocarcinoma tumours, since this model is 137 considered a standard and has been demonstrated by many laboratories as 138 anti-PDL1-sensitive and immunogenic.
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