NK细胞耗竭与卡控点免疫治疗
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摘要
天然杀伤细胞(NK细胞)作为宿主免疫的第一道防线,通过直接抗肿瘤或辅助T细胞等方式,在抗肿瘤免疫应答过程中发挥重要作用。然而NK细胞在肿瘤微环境中往往处于功能低下的免疫耗竭状态,伴随着异常表达的细胞表面受体谱系,限制着NK细胞效应功能的发挥。NK细胞的卡控点免疫治疗作为肿瘤治疗的崭新思路,主要通过阻断NK细胞表面抑制性受体,解除NK细胞在肿瘤局部接收到的抑制性信号,逆转NK细胞的肿瘤免疫耗竭状态,从而触发抗肿瘤效应。随着研究的深入,我们将进一步揭示NK细胞特定卡控点分子的作用机理、适应证及生物标志物,从而充分发挥NK细胞卡控点免疫治疗的潜力。
As the first line of defense of the host immune system,natural killer cells play important roles in anti-tumor immunity,either by direct anti-tumor effects,or by assisting T cell immune responses. However,NK cells are usually functionally exhausted in tumor microenvironment,accompanied with dysregulated expression of an array of surface receptors,restricting the effector potentials of NK cells. NK-based checkpoint immunotherapy aims to trigger anti-tumor efficacy by blocking NK cell surface inhibitory receptors,unleashing NK cells from inhibitory signals of the tumor microenvironment,and reversing NK cell exhaustion,representing a novel strategy in cancer therapy. With more in-depth research to reveal the mechanisms of action,indications,and biomarkers for specific NK cell checkpoint molecules,we shall fully exploit the potentials of NK-based checkpoint blockade immunotherapy.
As the first line of defense of the host immune system,natural killer cells play important roles in anti-tumor immunity,either by direct anti-tumor effects,or by assisting T cell immune responses. However,NK cells are usually functionally exhausted in tumor microenvironment,accompanied with dysregulated expression of an array of surface receptors,restricting the effector potentials of NK cells. NK-based checkpoint immunotherapy aims to trigger anti-tumor efficacy by blocking NK cell surface inhibitory receptors,unleashing NK cells from inhibitory signals of the tumor microenvironment,and reversing NK cell exhaustion,representing a novel strategy in cancer therapy. With more in-depth research to reveal the mechanisms of action,indications,and biomarkers for specific NK cell checkpoint molecules,we shall fully exploit the potentials of NK-based checkpoint blockade immunotherapy.
引文
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[3]Bi J,Tian Z.NK Cell Exhaustion[J].Front Immunol,2017,8:760.
[4]Young JD,Hengartner H,Podack ER,et al.Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity[J].Cell,1986,44(6):849-859.
[5]Montel AH,Bochan MR,Hobbs JA,et al.Fas involvement in cytotoxicity mediated by human NK cells[J].Cell Immunol,1995,166(2):236-246.
[6]Zamai L,Ahmad M,Bennett IM,et al.Natural killer(NK)cell-mediated cytotoxicity:differential use of TRAIL and Fas ligand by immature and mature primary human NK cells[J].J Exp Med,1998,188(12):2375-2380.
[7]Stetson DB,Mohrs M,Reinhardt RL,et al.Constitutive cytokine mRNAs mark natural killer(NK)and NK T cells poised for rapid effector function[J].J Exp Med,2003,198(7):1069-1076.
[8]Kaplan DH,Shankaran V,Dighe AS,et al.Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice[J].Proc Natl Acad Sci U S A,1998,95(13):7556-7561.
[9]Smyth MJ,Kelly JM,Baxter AG,et al.An essential role for tumor necrosis factor in natural killer cell-mediated tumor rejection in the peritoneum[J].J Exp Med,1998,188(9):1611-1619.
[10]Braumuller H,Wieder T,Brenner E,et al.T-helper-1-cell cytokines drive cancer into senescence[J].Nature,2013,494(7437):361-365.
[11]Martin-Fontecha A,Thomsen LL,Brett S,et al.Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming[J].Nat Immunol,2004,5(12):1260-1265.
[12]Mocikat R,Braumuller H,Gumy A,et al.Natural killer cells activated by MHC class I(low)targets prime dendritic cells to induce protective CD8 T cell responses[J].Immunity,2003,19(4):561-569.
[13]Vivier E,Ugolini S,Blaise D,et al.Targeting natural killer cells and natural killer T cells in cancer[J].Nat Rev Immunol,2012,12(4):239-252.
[14]Messaoudene M,Fregni G,Fourmentraux-Neves E,et al.Mature cytotoxic CD56(bright)/CD16(+)natural killer cells can infiltrate lymph nodes adjacent to metastatic melanoma[J].Cancer Res,2014,74(1):81-92.
[15]Smyth MJ,Thia KY,Cretney E,et al.Perforin is a major contributor to NK cell control of tumor metastasis[J].J Immunol,1999,162(11):6658-6662.
[16]Street SE,Cretney E,Smyth MJ.Perforin and interferon-gamma activities independently control tumor initiation,growth,and metastasis[J].Blood,2001,97(1):192-197.
[17]Glasner A,Levi A,Enk J,et al.NKp46 receptor-mediated interferon-gamma production by natural killer cells increases fibronectin1 to alter tumor architecture and control metastasis[J].Immunity,2018,48(1):107-119.
[18]Takeda K,Hayakawa Y,Smyth MJ,et al.Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells[J].Nat Med,2001,7(1):94-100.
[19]Chockley PJ,Chen J,Chen G,et al.Epithelial-mesenchymal transition leads to NK cell-mediated metastasis-specific immunosurveillance in lung cancer[J].J Clin Invest,2018,128(4):1384-1396.
[20]Concha-Benavente F,Kansy B,Moskovitz J,et al.PD-L1 mediates dysfunction in activated PD-1(+)NK cells in head and neck cancer patients[J].Cancer Immunol Res,2018,6(12):1548-1560.
[21]Coca S,Perez-Piqueras J,Martinez D,et al.The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma[J].Cancer,1997,79(12):2320-2328.
[22]Ishigami S,Natsugoe S,Tokuda K,et al.Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer[J].Cancer Letters,2000,159(1):103-108.
[23]Villegas FR,Coca S,Villarrubia VG,et al.Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer[J].Lung Cancer,2002,35(1):23-28.
[24]Paul S,Kulkarni N,Shilpi,et al.Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells[J].Oncoimmunology,2016,5(12):e1235106.
[25]Zhang Q,Bi J,Zheng X,et al.Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity[J].Nat Immunol,2018,19(7):723-732.
[26]Barry KC,Hsu J,Broz ML,et al.A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments[J].Nat Med,2018,24(8):1178-1191.
[27]Guillerey C,Ferrari de Andrade L,Vuckovic S,et al.Immunosurveillance and therapy of multiple myeloma are CD226 dependent[J].J Clin Invest,2015,125(7):2904.
[28]Platonova S,Cherfils-Vicini J,Damotte D,et al.Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma[J].Cancer Res,2011,71(16):5412-5422.
[29]Sun C,Xu J,Huang Q,et al.High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer[J].Oncoimmunology,2017,6(1):e1264562.
[30]Mamessier E,Sylvain A,Thibult ML,et al.Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity[J].J Clin Invest,2011,121(9):3609-3622.
[31]Peng YP,Zhu Y,Zhang JJ,et al.Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer,gastric cancer,and colorectal cancer[J].J Translational Med,2013,11:262.
[32]Gill S,Vasey AE,De Souza A,et al.Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells[J].Blood,2012,119(24):5758-5768.
[33]Yu X,Harden K,Gonzalez LC,et al.The surface protein TIGITsuppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells[J].Nat Immunol,2009,10(1):48-57.
[34]Stanietsky N,Simic H,Arapovic J,et al.The interaction of TIGITwith PVR and PVRL2 inhibits human NK cell cytotoxicity[J].Proc Natl Acad Sci U S A,2009,106(42):17858-17863.
[35]Liu S,Zhang H,Li M,et al.Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells[J].Cell Death Differentiation,2013,20(3):456-464.
[36]Lozano E,Dominguez-Villar M,Kuchroo V,et al.The TIGIT/CD226 axis regulates human T cell function[J].J Immunol,2012,188(8):3869-3875.
[37]Johnston RJ,Comps-Agrar L,Hackney J,et al.The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+)T cell effector function[J].Cancer Cell,2014,26(6):923-937.
[38]Stanietsky N,Rovis TL,Glasner A,et al.Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR[J].Eur J Immunol,2013,43(8):2138-2150.
[39]Li M,Xia P,Du Y,et al.T-cell immunoglobulin and ITIM domain(TIGIT)receptor/poliovirus receptor(PVR)ligand engagement suppresses interferon-gamma production of natural killer cells via beta-arrestin 2-mediated negative signaling[J].J Biological Chem,2014,289(25):17647-17657.
[40]Bi J,Zhang Q,Liang D,et al.T-cell Ig and ITIM domain regulates natural killer cell activation in murine acute viral hepatitis[J].Hepatology,2014,59(5):1715-1725.
[41]Bi J,Zheng X,Chen Y,et al.TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk[J].Hepatology,2014,60(4):1389-1398.
[42]Fuchs A,Cella M,Giurisato E,et al.Cutting edge:CD96(tactile)promotes NK cell-target cell adhesion by interacting with the poliovirus receptor(CD155)[J].J Immunol,2004,172(7):3994-3998.
[43]Chan CJ,Martinet L,Gilfillan S,et al.The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions[J].Nat Immunol,2014,15(5):431-438.
[44]Sun H,Huang Q,Huang M,et al.Human CD96 correlates to NKcell exhaustion and predicts the prognosis of human hepatocellular carcinoma[J].Hepatology,2018,doi:10.1002/hep.30347.[Epub ahead of print].
[45]Quatrini L,Wieduwild E,Escaliere B,et al.Endogenous glucocorticoids control host resistance to viral infection through the tissuespecific regulation of PD-1 expression on NK cells[J].Nat Immunol,2018,19(9):954-962.
[46]Huntington ND,Legrand N,Alves NL,et al.IL-15 transpresentation promotes human NK cell development and differentiation in vivo[J].J Exp Med,2009,206(1):25-34.
[47]Ranson T,Vosshenrich CA,Corcuff E,et al.IL-15 is an essential mediator of peripheral NK-cell homeostasis[J].Blood,2003,101(12):4887-4893.
[48]Richards JO,Chang X,Blaser BW,et al.Tumor growth impedes natural-killer-cell maturation in the bone marrow[J].Blood,2006,108(1):246-252.
[49]Pitt JM,Vetizou M,Daillere R,et al.Resistance mechanisms to immune-checkpoint blockade in cancer:tumor-intrinsic and-extrinsic factors[J].Immunity,2016,44(6):1255-1269.
[50]Ruggeri L,Capanni M,Urbani E,et al.Effectiveness of donor natural killer cell allore activity in mismatched hematopoietic transplants[J].Science,2002,295(5562):2097-2100.
[51]Blake SJ,Stannard K,Liu J,et al.Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy[J].Cancer Discovery,2016,6(4):446-459.
[52]Roman Aguilera A,Lutzky VP,Mittal D,et al.CD96 targeted antibodies need not block CD96-CD155 interactions to promote NKcell anti-metastatic activity[J].Oncoimmunology,2018,7(5):e1424677.
[53]Andre P,Denis C,Soulas C,et al.Anti-NKG2A m Ab is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells[J].Cell,2018,175(7):1731-1743.
[54]van Montfoort N,Borst L,Korrer MJ,et al.NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines[J].Cell,2018,175(7):1744-1755.
[2]Vivier E,Tomasello E,Baratin M,et al.Funct natural killer cells[J].Nat Immunol,2008,9(5):503-510.
[3]Bi J,Tian Z.NK Cell Exhaustion[J].Front Immunol,2017,8:760.
[4]Young JD,Hengartner H,Podack ER,et al.Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity[J].Cell,1986,44(6):849-859.
[5]Montel AH,Bochan MR,Hobbs JA,et al.Fas involvement in cytotoxicity mediated by human NK cells[J].Cell Immunol,1995,166(2):236-246.
[6]Zamai L,Ahmad M,Bennett IM,et al.Natural killer(NK)cell-mediated cytotoxicity:differential use of TRAIL and Fas ligand by immature and mature primary human NK cells[J].J Exp Med,1998,188(12):2375-2380.
[7]Stetson DB,Mohrs M,Reinhardt RL,et al.Constitutive cytokine mRNAs mark natural killer(NK)and NK T cells poised for rapid effector function[J].J Exp Med,2003,198(7):1069-1076.
[8]Kaplan DH,Shankaran V,Dighe AS,et al.Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice[J].Proc Natl Acad Sci U S A,1998,95(13):7556-7561.
[9]Smyth MJ,Kelly JM,Baxter AG,et al.An essential role for tumor necrosis factor in natural killer cell-mediated tumor rejection in the peritoneum[J].J Exp Med,1998,188(9):1611-1619.
[10]Braumuller H,Wieder T,Brenner E,et al.T-helper-1-cell cytokines drive cancer into senescence[J].Nature,2013,494(7437):361-365.
[11]Martin-Fontecha A,Thomsen LL,Brett S,et al.Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming[J].Nat Immunol,2004,5(12):1260-1265.
[12]Mocikat R,Braumuller H,Gumy A,et al.Natural killer cells activated by MHC class I(low)targets prime dendritic cells to induce protective CD8 T cell responses[J].Immunity,2003,19(4):561-569.
[13]Vivier E,Ugolini S,Blaise D,et al.Targeting natural killer cells and natural killer T cells in cancer[J].Nat Rev Immunol,2012,12(4):239-252.
[14]Messaoudene M,Fregni G,Fourmentraux-Neves E,et al.Mature cytotoxic CD56(bright)/CD16(+)natural killer cells can infiltrate lymph nodes adjacent to metastatic melanoma[J].Cancer Res,2014,74(1):81-92.
[15]Smyth MJ,Thia KY,Cretney E,et al.Perforin is a major contributor to NK cell control of tumor metastasis[J].J Immunol,1999,162(11):6658-6662.
[16]Street SE,Cretney E,Smyth MJ.Perforin and interferon-gamma activities independently control tumor initiation,growth,and metastasis[J].Blood,2001,97(1):192-197.
[17]Glasner A,Levi A,Enk J,et al.NKp46 receptor-mediated interferon-gamma production by natural killer cells increases fibronectin1 to alter tumor architecture and control metastasis[J].Immunity,2018,48(1):107-119.
[18]Takeda K,Hayakawa Y,Smyth MJ,et al.Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells[J].Nat Med,2001,7(1):94-100.
[19]Chockley PJ,Chen J,Chen G,et al.Epithelial-mesenchymal transition leads to NK cell-mediated metastasis-specific immunosurveillance in lung cancer[J].J Clin Invest,2018,128(4):1384-1396.
[20]Concha-Benavente F,Kansy B,Moskovitz J,et al.PD-L1 mediates dysfunction in activated PD-1(+)NK cells in head and neck cancer patients[J].Cancer Immunol Res,2018,6(12):1548-1560.
[21]Coca S,Perez-Piqueras J,Martinez D,et al.The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma[J].Cancer,1997,79(12):2320-2328.
[22]Ishigami S,Natsugoe S,Tokuda K,et al.Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer[J].Cancer Letters,2000,159(1):103-108.
[23]Villegas FR,Coca S,Villarrubia VG,et al.Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer[J].Lung Cancer,2002,35(1):23-28.
[24]Paul S,Kulkarni N,Shilpi,et al.Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells[J].Oncoimmunology,2016,5(12):e1235106.
[25]Zhang Q,Bi J,Zheng X,et al.Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity[J].Nat Immunol,2018,19(7):723-732.
[26]Barry KC,Hsu J,Broz ML,et al.A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments[J].Nat Med,2018,24(8):1178-1191.
[27]Guillerey C,Ferrari de Andrade L,Vuckovic S,et al.Immunosurveillance and therapy of multiple myeloma are CD226 dependent[J].J Clin Invest,2015,125(7):2904.
[28]Platonova S,Cherfils-Vicini J,Damotte D,et al.Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma[J].Cancer Res,2011,71(16):5412-5422.
[29]Sun C,Xu J,Huang Q,et al.High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer[J].Oncoimmunology,2017,6(1):e1264562.
[30]Mamessier E,Sylvain A,Thibult ML,et al.Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity[J].J Clin Invest,2011,121(9):3609-3622.
[31]Peng YP,Zhu Y,Zhang JJ,et al.Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer,gastric cancer,and colorectal cancer[J].J Translational Med,2013,11:262.
[32]Gill S,Vasey AE,De Souza A,et al.Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells[J].Blood,2012,119(24):5758-5768.
[33]Yu X,Harden K,Gonzalez LC,et al.The surface protein TIGITsuppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells[J].Nat Immunol,2009,10(1):48-57.
[34]Stanietsky N,Simic H,Arapovic J,et al.The interaction of TIGITwith PVR and PVRL2 inhibits human NK cell cytotoxicity[J].Proc Natl Acad Sci U S A,2009,106(42):17858-17863.
[35]Liu S,Zhang H,Li M,et al.Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells[J].Cell Death Differentiation,2013,20(3):456-464.
[36]Lozano E,Dominguez-Villar M,Kuchroo V,et al.The TIGIT/CD226 axis regulates human T cell function[J].J Immunol,2012,188(8):3869-3875.
[37]Johnston RJ,Comps-Agrar L,Hackney J,et al.The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+)T cell effector function[J].Cancer Cell,2014,26(6):923-937.
[38]Stanietsky N,Rovis TL,Glasner A,et al.Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR[J].Eur J Immunol,2013,43(8):2138-2150.
[39]Li M,Xia P,Du Y,et al.T-cell immunoglobulin and ITIM domain(TIGIT)receptor/poliovirus receptor(PVR)ligand engagement suppresses interferon-gamma production of natural killer cells via beta-arrestin 2-mediated negative signaling[J].J Biological Chem,2014,289(25):17647-17657.
[40]Bi J,Zhang Q,Liang D,et al.T-cell Ig and ITIM domain regulates natural killer cell activation in murine acute viral hepatitis[J].Hepatology,2014,59(5):1715-1725.
[41]Bi J,Zheng X,Chen Y,et al.TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk[J].Hepatology,2014,60(4):1389-1398.
[42]Fuchs A,Cella M,Giurisato E,et al.Cutting edge:CD96(tactile)promotes NK cell-target cell adhesion by interacting with the poliovirus receptor(CD155)[J].J Immunol,2004,172(7):3994-3998.
[43]Chan CJ,Martinet L,Gilfillan S,et al.The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions[J].Nat Immunol,2014,15(5):431-438.
[44]Sun H,Huang Q,Huang M,et al.Human CD96 correlates to NKcell exhaustion and predicts the prognosis of human hepatocellular carcinoma[J].Hepatology,2018,doi:10.1002/hep.30347.[Epub ahead of print].
[45]Quatrini L,Wieduwild E,Escaliere B,et al.Endogenous glucocorticoids control host resistance to viral infection through the tissuespecific regulation of PD-1 expression on NK cells[J].Nat Immunol,2018,19(9):954-962.
[46]Huntington ND,Legrand N,Alves NL,et al.IL-15 transpresentation promotes human NK cell development and differentiation in vivo[J].J Exp Med,2009,206(1):25-34.
[47]Ranson T,Vosshenrich CA,Corcuff E,et al.IL-15 is an essential mediator of peripheral NK-cell homeostasis[J].Blood,2003,101(12):4887-4893.
[48]Richards JO,Chang X,Blaser BW,et al.Tumor growth impedes natural-killer-cell maturation in the bone marrow[J].Blood,2006,108(1):246-252.
[49]Pitt JM,Vetizou M,Daillere R,et al.Resistance mechanisms to immune-checkpoint blockade in cancer:tumor-intrinsic and-extrinsic factors[J].Immunity,2016,44(6):1255-1269.
[50]Ruggeri L,Capanni M,Urbani E,et al.Effectiveness of donor natural killer cell allore activity in mismatched hematopoietic transplants[J].Science,2002,295(5562):2097-2100.
[51]Blake SJ,Stannard K,Liu J,et al.Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy[J].Cancer Discovery,2016,6(4):446-459.
[52]Roman Aguilera A,Lutzky VP,Mittal D,et al.CD96 targeted antibodies need not block CD96-CD155 interactions to promote NKcell anti-metastatic activity[J].Oncoimmunology,2018,7(5):e1424677.
[53]Andre P,Denis C,Soulas C,et al.Anti-NKG2A m Ab is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells[J].Cell,2018,175(7):1731-1743.
[54]van Montfoort N,Borst L,Korrer MJ,et al.NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines[J].Cell,2018,175(7):1744-1755.