新型IFN-α/anti-PD-L1融合蛋白通过活化肿瘤特异性CD8~+T淋巴细胞促进抗肿瘤疗效
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摘要
共抑制和共刺激通路对T淋巴细胞活化都是至关重要的,调节这些通路的抗体都是十分有前景的肿瘤治疗候选物。虽然阻断PD-L1、PD-1和CTLA-4的抗体在一些肿瘤患者中取得了良好的效果,但仍有约70%的患者对这些治疗反应不佳。许多内在机制,特别是低肿瘤突变负荷和有限数量的肿瘤浸润淋巴细胞是造成该耐药性的主要原因。为克服这些因素,课题组设计了新型IFN-α/anti-PD-L1融合蛋白,其可以同时增加肿瘤浸润淋巴细胞数量并阻断PD-1-PD-L1免疫抑制通路。IFN-α/anti-PD-L1融合蛋白在体内外均显示出活化T淋巴细胞能力,这有助于后者提高有效的体内抗肿瘤活性。综上,课题组视IFN-α/anti-PD-L1融合蛋白应用于临床为肿瘤免疫治疗新策略。
Both co-inhibitory and co-stimulatory pathways are critical for T cell activation, and antibodies that modulate these pathways are promising cancer therapeutic drug candidates. Indeed, blocking antibodies against PD-L1, PD-1 and CTLA-4 have achieved good results in some cancer patients. However, about 70% of patients do not respond well to these treatments. A lot of intrinsic mechanisms, especially low tumor mutation burden and limited tumor infiltrating lymphocytes contribute to the treatment resistance. To overcome these limitations, we designed an IFN-α/anti-PD-L1 fusion protein, which can simultaneously increase tumor infiltrating lymphocytes and block co-inhibitory PD-1-PD-L1 pathway. The IFN-α/anti-PD-L1 fusion protein showed T cell activating ability both in vitro and in vivo, which contributes to its potent anti-tumor activity in vivo. Taken together, our data indicate that IFN-α/anti-PD-L1 fusion protein may be a new strategy for cancer immunotherapy.
Both co-inhibitory and co-stimulatory pathways are critical for T cell activation, and antibodies that modulate these pathways are promising cancer therapeutic drug candidates. Indeed, blocking antibodies against PD-L1, PD-1 and CTLA-4 have achieved good results in some cancer patients. However, about 70% of patients do not respond well to these treatments. A lot of intrinsic mechanisms, especially low tumor mutation burden and limited tumor infiltrating lymphocytes contribute to the treatment resistance. To overcome these limitations, we designed an IFN-α/anti-PD-L1 fusion protein, which can simultaneously increase tumor infiltrating lymphocytes and block co-inhibitory PD-1-PD-L1 pathway. The IFN-α/anti-PD-L1 fusion protein showed T cell activating ability both in vitro and in vivo, which contributes to its potent anti-tumor activity in vivo. Taken together, our data indicate that IFN-α/anti-PD-L1 fusion protein may be a new strategy for cancer immunotherapy.
引文
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[26]Yang X,Zhang X,Fu ML,et al.Targeting the tumor microenvironment with interferon-βbridges innate and adaptive immune responses[J].Cancer Cell,2014,25(1):37-48.
[2]Chen L,Han X.Anti-PD-1/PD-L1therapy of human cancer:Past,present,and future[J].J Clin Invest,2015,125(9):3384-3391.
[3]Alsaab HO,Sau S,Alzhrani R,et al.PD-1and PD-L1checkpoint signaling inhibition for cancer immunotherapy:Mechanism,combinations,and clinical outcome[J].Front Pharmacol,2017,8:561.
[4]Wang Q,Wu X.Primary and acquired resistance to PD-1/PD-L1blockade in cancer treatment[J].Int Immunopharmacol,2017,46:210-219.
[5]闵慜,吴霞.PD-1/PD-L1阻断治疗及其疗效预测研究进展[J].现代免疫学,2018,38(3):261-265.
[6]Kirkwood JM,Butterfield LH,Tarhini AA,et al.Immunotherapy of cancer in 2012[J].CA Cancer J Clin,2012,62(5):309-335.
[7]Theofilopoulos AN,Baccala R,Beutler B,et al.TypeⅠinterferons(alpha/beta)in immunity and autoimmunity[J].Ann Rev Immunol,2005,23:307-336.
[8]Stetson DB,Medzhitov R.TypeⅠinterferons in host defense[J].Immunity,2006,25(3):373-381.
[9]Gogas H,Ioannovich J,Dafni U,et al.Prognostic significance of autoimmunity during treatment of melanoma with interferon[J].N Engl J Med,2006,354(7):709-718.
[10]Dunn GP,Koebel CM,Schreiber RD.Interferons,immunity and cancer immunoediting[J].Nat Rev Immunol,2006,6(11):836-848.
[11]Colonna M,Trinchieri G,Liu YJ.Plasmacytoid dendritic cells in immunity[J].Nat Immunol,2004,5(12):1219-1226.
[12]Kirkwood J.Cancer immunotherapy:The interferon-alpha experience[J].Semin Oncol,2002,29(3Suppl 7):18-26.
[13]Cho HJ,Hayashi T,Datta SK,et al.IFN-alpha beta promote priming of antigen-specific CD8+and CD4+T lymphocytes by immunostimulatory DNA-based vaccines[J].J Immunol,2002,168(10):4907-4913.
[14]Le Bon A,Durand V,Kamphuis E,et al.Direct stimulation of T cells by typeⅠIFN enhances the CD8+T cell response during cross-priming[J].J Immunol,2006,176(8):4682-4689.
[15]Terawaki S,Chikuma S,Shibayama S,et al.IFN-αdirectly promotes programmed cell death-1transcription and limits the duration of T cell-mediated immunity[J].J Immunol,2011,186(5):2772-2779.
[16]Tang H,Wang Y,Chlewicki LK,et al.Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1blockade[J].Cancer Cell,2016,29(3):285-296.
[17]Boon T,Coulie PG,van den Eynde BT,et al.Human T cell responses against melanoma[J].Annu Rev Immunol,2006,24:175-208.
[18]Segal NH,Parsons DW,Peggs KS,et al.Epitope landscape in breast and colorectal cancer[J].Cancer Res,2008,68(3):889-892.
[19]Palucka K,Banchereau J,Mellman I.Designing vaccines based on biology of human dendritic cell subsets[J].Immunity,2010,33(4):464-478.
[20]Wilcox RA,Feldman AL,Wada DA,et al.B7-H1(PD-L1,CD274)suppresses host immunity in T-cell lymphoproliferative disorders[J].Blood,2009,114(10):2149-2158.
[21]Zhang X,Cheng C,Hou J,et al.Distinct contribution of PD-L1suppression by spatial expression of PD-L1on tumor and non-tumor cells[J].Cell Mol Immunol,2018.
[22]Kooi S,Zhang HZ,Patenia R,et al.HLA classⅠexpression on human ovarian carcinoma cells correlates with T-cell infiltration in vivo and T-cell expansion in vitro in low concentrations of recombinant interleukin-2[J].Cell Immunol,1996,174(2):116-128.
[23]Hamanishi J,Mandai M,Iwasaki M,et al.Programmed cell death 1ligand 1and tumor-infiltrating CD8+T lymphocytes are prognostic factors of human ovarian cancer[J].Proc Natl Acad Sci U S A,2007,104(9):3360-3365.
[24]Ivashkiv LB,Donlin LT.Regulation of typeⅠinterferon responses[J].Nat Rev Immunol,2014,14(1):36-49.
[25]Belardelli F,Ferrantini M,Proietti E,et al.Interferon-alpha in tumor immunity and immunotherapy[J].Cytokine Growth Factor Rev,2002,13(2):119-134.
[26]Yang X,Zhang X,Fu ML,et al.Targeting the tumor microenvironment with interferon-βbridges innate and adaptive immune responses[J].Cancer Cell,2014,25(1):37-48.