胰腺癌的免疫治疗研究进展
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摘要
胰腺癌是世界上致死率最高的恶性肿瘤之一,早期诊断困难,多数患者确诊时已失去手术机会,且对放化疗治疗不敏感,造成临床治疗上面临很多困难。近年来,肿瘤免疫治疗已成为肿瘤学领域的热点,在胰腺癌的治疗方面也取得了较大的进展。目前已出现多种免疫治疗策略,包括主动免疫、被动免疫、免疫检查点抑制剂、嵌合抗原受体T细胞和其他免疫调节策略等。胰腺癌细胞的一大特点是其表面表达大量肿瘤相关抗原,适宜于疫苗的靶向作用。因此,癌症疫苗成为一种有希望的新型治疗方法。
Pancreatic cancer is one of the most fatal malignant tumors in the world. It is difficult to be diagnosed early. Most patients have lost their chance of surgery at the time of diagnosis and are not sensitive to radiotherapy and chemotherapy. This has caused lots of difficulties in clinical treatment. In recent years, tumor immunotherapy has become a hot spot in the field of oncology, and great progress has been made in the treatment of pancreatic cancer. A variety of immunotherapeuticstrategies have emerged, including active immunization, passive immunization, immunological checkpoint inhibitors, chimeric antigen receptor T cells, and other immunomodulatory strategies. A major feature of pancreatic cancer cells is that they express a large number of tumor-associated antigens on their surface, which is suitable for the targeting of vaccines. Therefore, cancer vaccines have become a promising new treatment.
Pancreatic cancer is one of the most fatal malignant tumors in the world. It is difficult to be diagnosed early. Most patients have lost their chance of surgery at the time of diagnosis and are not sensitive to radiotherapy and chemotherapy. This has caused lots of difficulties in clinical treatment. In recent years, tumor immunotherapy has become a hot spot in the field of oncology, and great progress has been made in the treatment of pancreatic cancer. A variety of immunotherapeuticstrategies have emerged, including active immunization, passive immunization, immunological checkpoint inhibitors, chimeric antigen receptor T cells, and other immunomodulatory strategies. A major feature of pancreatic cancer cells is that they express a large number of tumor-associated antigens on their surface, which is suitable for the targeting of vaccines. Therefore, cancer vaccines have become a promising new treatment.
引文
[1] LIU Q, LIAO Q, ZHAO Y. Chemotherapy and tumor microenvironment of pancreatic cancer[J]. Cancer Cell Int, 2017, 17(68):64-68.
[2] KAMISAWA T, WOOD LD, ITOI T, et al. Pancreatic cancer[J].Lancet, 2016, 388(10039):73-85.
[3]彭美玉,郭振涛.免疫细胞在胰腺癌发生发展中的作用[J].中国肿瘤, 2018, 27(4):294-298.
[4] DUNN GP, BRUCE AT, IKEDA H, et al. Cancer immunoediting:from immunosurveillance to tumor escape[J]. Nat Immunol, 2002, 3(11):991-998.
[5] GABITASS RF, ANNELS NE, STOCKEN DD, et al. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13[J]. Cancer ImmunolImmunother, 2011, 60(10):1419-1430.
[6] LUTZ E, YEO CJ, LILLEMOE KD, et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A PhaseⅡtrial of safety, efficacy, and immune activation[J]. Ann Surg, 2011, 253(2):328-335.
[7] LE DT, BROCKSTEDT DG, NIR-PAZR, et al. A live-attenuated Listeria vaccine(ANZ-100)and a live-attenuated Listeria vaccine expressing mesothelin(CRS-207)for advanced cancers:phase I studies of safety and immune induction[J]. Clin CancerRes, 2012, 18(3):858-868.
[8] SPRINGETT GM. Novel pancreatic cancer vaccines could unleash the army within[J]. Cancer Control, 2014, 21(3):242-246.
[9] LE DT, LUTZ E, LAHERU DA, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer[J]. J Immunother, 2013, 36(7):382-389.
[10]张美静,王斌,湛先保.胰腺癌免疫治疗的研究进展[J].中国肿瘤生物治疗杂志, 2018, 25(3):288-292.
[11] HARDACRE JM, MULCAHY M, SMALL W, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer:a phase 2 study[J]. J GastrointestSurg, 2013, 17(1):94-101.
[12] COVELER AL, ROSSI GR, VAHANIAN NN, et al. Algenpantucel-L immunotherapy in pancreatic adenocarcinoma[J]. Immunotherapy,2016, 8:117-125.
[13]刘文增.胰腺癌的肿瘤微环境及其免疫治疗研究进展[A].中国免疫学会.第十三届全国免疫学学术大会摘要汇编[C].中国免疫学会:中国免疫学会, 2018:2.
[14] ABOU-ALFA GK, CHAPMAN PB, FEILCHENFELDT J, et al. Targeting mutated K-ras in Pancreatic adenocarcinoma using an adjuvant vaccine[J]. Am J Clin Oncol, 2011, 34:321-325.
[15]刘文婷,姜广水.树突状细胞对调节性T细胞的调控作用[J].国际免疫学杂志, 2012, 35(3):172-175.
[16]吴行,王小明.胰腺癌的免疫治疗研究进展[J].山东医药, 2017, 57(8):102-105.
[17] LUTZ E, YEO CJ, LILLEMOE KD, et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma:A phaseⅡtrial of safety, efficacy, and immune activation[J]. Ann Surg, 2011, 253(2):328-335.
[18] LE DT, WANG-GILLAM A, PICOZZI V, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin(CRS-207)boost vaccines for metastatic pancreatic cancer[J]. Journal of Clinical Oncology, 2015, 33(12):1325-1333.
[19] ROULOIS D, GRéGOIRE M, FONTENEAU JF. MUC1-specific cytotoxic T lymphocytes in cancer therapy:induction and challenge[J].Biomed Res Int, 2013, 2013:871936.
[20] QU CF, LI Y, SONG YJ, et al. MUC1 expression in primary and metastatic pancreatic cancer cells for in vitro treatment by(213)Bi-C595radioimmunoconjugate[J]. Br J Cancer, 2004, 91(12):2086-2093.
[21] GOLD DV, MODRAK DE, SCHUTSKY K, et al. Combined 90Yttrium DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft[J]. Int J Cancer, 2004, 109(4):618-626.
[22] WATKINS DJ, STARLING N, CUNNINGHAM D, et al. The combination of a chemotherapy doublet(gemcitabine and capecitabine)with a biological doublet(bevacizumab and erlotinib)in patients with advanced pancreatic adenocarcinoma. The results of a phaseⅠ/Ⅱstudy[J]. Eur J Cancer, 2014, 50(8):1422-1429.
[23] WALSH N, KENNEDY S, LARKIN A, et al. EDFR and HER2 inhibition in pancreatic cancer[J]. Invest New Drugs, 2013, 31(3):558-566.
[24] YARDEN Y, SLIWKOWSKI MX. Untangling the erb signalling network[J]. Nat Rev Mol Cell Biol, 2001, 2(2):127-137.
[25] FRIEDMAN LM, RINON A, SCHECHTER B, et al. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs:implications for cancer immunotherapy[J]. Proc Natl Acad Sci USA, 2005, 102(6):1915-1920.
[26] LARBOURET C, ROBERT B, BASCOUL-MOLLEVI C, et al. Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts[J]. Ann Oncol,2009, 21(1):98-103.
[27] BELTRAN PJ, MITCHELL P, CHUNG YA, et al. AMG 479, a fully human anti-insulin-like growth factor receptor typeⅠmonoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells[J]. Mol Cancer Ther, 2009, 8:1095-1105.
[28] MCCAFFERY I, TUDOR Y, DENG H, et al. Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor[J]. Clin Cancer Res, 2013, 19(15):4282-4289.
[29] FURUSE J. Pancreatic cancer:is combination treatment better?[J].ClinPract, 2013, 10:695-700.
[30] PHILIP PA, GOLDMAN B, BLANKE CD, et al. Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer:phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib(SWOG S0727)[J]. Cancer, 2014, 120:2980-2985.
[31] SHIN DH, MIN HY, EL-NAGGAR AK, et al. Akt/mTOR counteract the antitumor activities of cixutumumab, an anti-insulin-like growth factor I receptor monoclonal antibody[J]. Mol Cancer Ther, 2011,10:2437-2448.
[32] DI RENZO MF, POULSOM R, OLIVERO M, et al. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer[J]. Cancer Res, 1995, 55(5):1129-1138.
[33] AVAN A, QUINT K, NICOLINI F, et al. Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer[J]. Curr Pharm Des, 2013, 19(5):940-950.
[34] AVAN A, CARETTI V, FUNEL N, et al. Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma[J].Cancer Res, 2013, 73(22):6745-6756.
[35]刘文增,胡渊,张彩.胰腺癌的肿瘤微环境及其免疫治疗研究进展[J].中国免疫学杂志, 2018, 34(12):1901-1906.
[36] BENGSCH F, KNOBLOCK DM, LIU A, et al. CTLA-4/CD80 pathway regulates T cell infltration into pancreatic cancer[J]. Cancer Immunol Immunother, 2017, 66(12):1609-1617.
[37] TAGGART D, ANDREOUT, SCOTT KJ, et al. Anti-PD-1/anti-CTLA-4 efficacy in melanomabrain metastases depends on extracranial disease and augmentation of CD8(+)T cell trafficking[J/OL]. ProcNatl Acad Sci USA, 2018, 115(7):E1540-E1549.
[38] FOKAS E, O'NEILL E, GORDON-WEEKS A, et al. Pancreatic ductal adenocarcinoma:from genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic[J]. Biochim Biophys Acta, 2015, 1855(1):61-82.
[39] HINGORANI SR, ZHENG L, BULLOCK AJ, et al. HALO202:RandomizedphaseⅡstudy of PEGPH20 plus nab-paclitaxel/gemcitabine versus nabpaclitaxel/gemcitabine in patients with untreated, metastatic pancreaticductaladenocarcinoma[J]. J Clin Oncol, 2018, 36(4):359-366.
[40] CHEN J, JIANG CC, JIN L, et al. Regulation of PD-L1:a novel role of pro-survival signaling in cancer[J]. Ann Oncol, 2016, 27:409-416.
[41] LUHESHI NM, COATES-ULRICHSEN J, WILKINSON RW, et al.Transformation ofthe tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model[J]. Oncotarget, 2016,7:18508-18520.
[42] RIBAS A, WOLCHOK JD. Cancer immunotherapy using checkpoint blockade[J]. Science, 2018, 359(6382):1350-1355.
[43]李俊昊,余天柱,高珊珊,等.程序性死亡受体-配体1(PD-L1)表达与可切除胰腺癌患者预后的关系[J].复旦学报(医学版), 2018, 45(6):788-792.
[44] POLLACK SM, HE Q, YEARLEY JH, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas[J]. Cancer, 2017, 123(17):3291-3304.
[45] ZHANG X, ZENG Y, QU Q, et al. PD-L1 induced by IFN-gamma from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer[J]. Int J Clin Oncol, 2017, 22(6):1-8.
[46] LUPINACCI RM, GOLOUDINA A, SVRCEK M, et al. Prevalence of microsatellite instability in intraductalpapillary mucinous neoplasms of the pancreas[J]. Gastroenterology, 2018, 154:1061-1065.
[47] BALLI D, RECH AJ, STANGER BZ, et al. Immune cytolyticactivity stratifies molecular subsets of human pancreatic cancer[J]. Clin Cancer Res, 2017, 23:3129-3138.
[48] DOMINGUEZ VM, NAVARRO AG, RAHMAN AM, et al. Identification of a natural killer cell receptor allele that prolongs survival of cytomegalovirus-positive glioblastomapatients[J]. Cancer Res, 2016,76(18):5326-5336.
[49] WANG E, WANG LC, TSAI CY, et al. Generation of potent T-cell immunotherapy for cancer using DAP12-based, multichain, chimeric immunoreceptors[J]. Cancer Immunol Res, 2015, 3(7):815.
[2] KAMISAWA T, WOOD LD, ITOI T, et al. Pancreatic cancer[J].Lancet, 2016, 388(10039):73-85.
[3]彭美玉,郭振涛.免疫细胞在胰腺癌发生发展中的作用[J].中国肿瘤, 2018, 27(4):294-298.
[4] DUNN GP, BRUCE AT, IKEDA H, et al. Cancer immunoediting:from immunosurveillance to tumor escape[J]. Nat Immunol, 2002, 3(11):991-998.
[5] GABITASS RF, ANNELS NE, STOCKEN DD, et al. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13[J]. Cancer ImmunolImmunother, 2011, 60(10):1419-1430.
[6] LUTZ E, YEO CJ, LILLEMOE KD, et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A PhaseⅡtrial of safety, efficacy, and immune activation[J]. Ann Surg, 2011, 253(2):328-335.
[7] LE DT, BROCKSTEDT DG, NIR-PAZR, et al. A live-attenuated Listeria vaccine(ANZ-100)and a live-attenuated Listeria vaccine expressing mesothelin(CRS-207)for advanced cancers:phase I studies of safety and immune induction[J]. Clin CancerRes, 2012, 18(3):858-868.
[8] SPRINGETT GM. Novel pancreatic cancer vaccines could unleash the army within[J]. Cancer Control, 2014, 21(3):242-246.
[9] LE DT, LUTZ E, LAHERU DA, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer[J]. J Immunother, 2013, 36(7):382-389.
[10]张美静,王斌,湛先保.胰腺癌免疫治疗的研究进展[J].中国肿瘤生物治疗杂志, 2018, 25(3):288-292.
[11] HARDACRE JM, MULCAHY M, SMALL W, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer:a phase 2 study[J]. J GastrointestSurg, 2013, 17(1):94-101.
[12] COVELER AL, ROSSI GR, VAHANIAN NN, et al. Algenpantucel-L immunotherapy in pancreatic adenocarcinoma[J]. Immunotherapy,2016, 8:117-125.
[13]刘文增.胰腺癌的肿瘤微环境及其免疫治疗研究进展[A].中国免疫学会.第十三届全国免疫学学术大会摘要汇编[C].中国免疫学会:中国免疫学会, 2018:2.
[14] ABOU-ALFA GK, CHAPMAN PB, FEILCHENFELDT J, et al. Targeting mutated K-ras in Pancreatic adenocarcinoma using an adjuvant vaccine[J]. Am J Clin Oncol, 2011, 34:321-325.
[15]刘文婷,姜广水.树突状细胞对调节性T细胞的调控作用[J].国际免疫学杂志, 2012, 35(3):172-175.
[16]吴行,王小明.胰腺癌的免疫治疗研究进展[J].山东医药, 2017, 57(8):102-105.
[17] LUTZ E, YEO CJ, LILLEMOE KD, et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma:A phaseⅡtrial of safety, efficacy, and immune activation[J]. Ann Surg, 2011, 253(2):328-335.
[18] LE DT, WANG-GILLAM A, PICOZZI V, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin(CRS-207)boost vaccines for metastatic pancreatic cancer[J]. Journal of Clinical Oncology, 2015, 33(12):1325-1333.
[19] ROULOIS D, GRéGOIRE M, FONTENEAU JF. MUC1-specific cytotoxic T lymphocytes in cancer therapy:induction and challenge[J].Biomed Res Int, 2013, 2013:871936.
[20] QU CF, LI Y, SONG YJ, et al. MUC1 expression in primary and metastatic pancreatic cancer cells for in vitro treatment by(213)Bi-C595radioimmunoconjugate[J]. Br J Cancer, 2004, 91(12):2086-2093.
[21] GOLD DV, MODRAK DE, SCHUTSKY K, et al. Combined 90Yttrium DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft[J]. Int J Cancer, 2004, 109(4):618-626.
[22] WATKINS DJ, STARLING N, CUNNINGHAM D, et al. The combination of a chemotherapy doublet(gemcitabine and capecitabine)with a biological doublet(bevacizumab and erlotinib)in patients with advanced pancreatic adenocarcinoma. The results of a phaseⅠ/Ⅱstudy[J]. Eur J Cancer, 2014, 50(8):1422-1429.
[23] WALSH N, KENNEDY S, LARKIN A, et al. EDFR and HER2 inhibition in pancreatic cancer[J]. Invest New Drugs, 2013, 31(3):558-566.
[24] YARDEN Y, SLIWKOWSKI MX. Untangling the erb signalling network[J]. Nat Rev Mol Cell Biol, 2001, 2(2):127-137.
[25] FRIEDMAN LM, RINON A, SCHECHTER B, et al. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs:implications for cancer immunotherapy[J]. Proc Natl Acad Sci USA, 2005, 102(6):1915-1920.
[26] LARBOURET C, ROBERT B, BASCOUL-MOLLEVI C, et al. Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts[J]. Ann Oncol,2009, 21(1):98-103.
[27] BELTRAN PJ, MITCHELL P, CHUNG YA, et al. AMG 479, a fully human anti-insulin-like growth factor receptor typeⅠmonoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells[J]. Mol Cancer Ther, 2009, 8:1095-1105.
[28] MCCAFFERY I, TUDOR Y, DENG H, et al. Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor[J]. Clin Cancer Res, 2013, 19(15):4282-4289.
[29] FURUSE J. Pancreatic cancer:is combination treatment better?[J].ClinPract, 2013, 10:695-700.
[30] PHILIP PA, GOLDMAN B, BLANKE CD, et al. Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer:phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib(SWOG S0727)[J]. Cancer, 2014, 120:2980-2985.
[31] SHIN DH, MIN HY, EL-NAGGAR AK, et al. Akt/mTOR counteract the antitumor activities of cixutumumab, an anti-insulin-like growth factor I receptor monoclonal antibody[J]. Mol Cancer Ther, 2011,10:2437-2448.
[32] DI RENZO MF, POULSOM R, OLIVERO M, et al. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer[J]. Cancer Res, 1995, 55(5):1129-1138.
[33] AVAN A, QUINT K, NICOLINI F, et al. Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer[J]. Curr Pharm Des, 2013, 19(5):940-950.
[34] AVAN A, CARETTI V, FUNEL N, et al. Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma[J].Cancer Res, 2013, 73(22):6745-6756.
[35]刘文增,胡渊,张彩.胰腺癌的肿瘤微环境及其免疫治疗研究进展[J].中国免疫学杂志, 2018, 34(12):1901-1906.
[36] BENGSCH F, KNOBLOCK DM, LIU A, et al. CTLA-4/CD80 pathway regulates T cell infltration into pancreatic cancer[J]. Cancer Immunol Immunother, 2017, 66(12):1609-1617.
[37] TAGGART D, ANDREOUT, SCOTT KJ, et al. Anti-PD-1/anti-CTLA-4 efficacy in melanomabrain metastases depends on extracranial disease and augmentation of CD8(+)T cell trafficking[J/OL]. ProcNatl Acad Sci USA, 2018, 115(7):E1540-E1549.
[38] FOKAS E, O'NEILL E, GORDON-WEEKS A, et al. Pancreatic ductal adenocarcinoma:from genetics to biology to radiobiology to oncoimmunology and all the way back to the clinic[J]. Biochim Biophys Acta, 2015, 1855(1):61-82.
[39] HINGORANI SR, ZHENG L, BULLOCK AJ, et al. HALO202:RandomizedphaseⅡstudy of PEGPH20 plus nab-paclitaxel/gemcitabine versus nabpaclitaxel/gemcitabine in patients with untreated, metastatic pancreaticductaladenocarcinoma[J]. J Clin Oncol, 2018, 36(4):359-366.
[40] CHEN J, JIANG CC, JIN L, et al. Regulation of PD-L1:a novel role of pro-survival signaling in cancer[J]. Ann Oncol, 2016, 27:409-416.
[41] LUHESHI NM, COATES-ULRICHSEN J, WILKINSON RW, et al.Transformation ofthe tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model[J]. Oncotarget, 2016,7:18508-18520.
[42] RIBAS A, WOLCHOK JD. Cancer immunotherapy using checkpoint blockade[J]. Science, 2018, 359(6382):1350-1355.
[43]李俊昊,余天柱,高珊珊,等.程序性死亡受体-配体1(PD-L1)表达与可切除胰腺癌患者预后的关系[J].复旦学报(医学版), 2018, 45(6):788-792.
[44] POLLACK SM, HE Q, YEARLEY JH, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas[J]. Cancer, 2017, 123(17):3291-3304.
[45] ZHANG X, ZENG Y, QU Q, et al. PD-L1 induced by IFN-gamma from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer[J]. Int J Clin Oncol, 2017, 22(6):1-8.
[46] LUPINACCI RM, GOLOUDINA A, SVRCEK M, et al. Prevalence of microsatellite instability in intraductalpapillary mucinous neoplasms of the pancreas[J]. Gastroenterology, 2018, 154:1061-1065.
[47] BALLI D, RECH AJ, STANGER BZ, et al. Immune cytolyticactivity stratifies molecular subsets of human pancreatic cancer[J]. Clin Cancer Res, 2017, 23:3129-3138.
[48] DOMINGUEZ VM, NAVARRO AG, RAHMAN AM, et al. Identification of a natural killer cell receptor allele that prolongs survival of cytomegalovirus-positive glioblastomapatients[J]. Cancer Res, 2016,76(18):5326-5336.
[49] WANG E, WANG LC, TSAI CY, et al. Generation of potent T-cell immunotherapy for cancer using DAP12-based, multichain, chimeric immunoreceptors[J]. Cancer Immunol Res, 2015, 3(7):815.