Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor
Peptide receptor radionuclide therapy (PRRT) is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs) via somatostatin receptors. Despite promising clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that 177Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy.
References
[1]
Kl？ppel, G.; Dege, K.; Remmele, W.; Kapran, Y.; Tuzlali, S.; Modlin, I.M. Siegfried oberndorfer: A tribute to his work and life between Munich, Kiel, Geneva, and Istanbul. Virchows Arch.？2007, 451, S3–S7, doi:10.1007/s00428-007-0462-z.
[2]
Modlin, I.M.; Lye, K.D.; Kidd, M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer？2003, 97, 934–959, doi:10.1002/cncr.11105.
[3]
Modlin, I.M.; Shapiro, M.D.; Kidd, M. An analysis of rare carcinoid tumors: Clarifying these clinical conundrums. World J. Surg.？2005, 29, 92–101, doi:10.1007/s00268-004-7443-z.
[4]
Kaltsas, G.A.; Besser, G.M.; Grossman, A.B. The diagnosis and medical management of advanced neuroendocrine tumors. Endocrine Rev.？2004, 25, 458–511, doi:10.1210/er.2003-0014.
[5]
Gustafsson, B.I.; Kidd, M.; Modlin, I.M. Neuroendocrine tumors of the diffuse neuroendocrine system. Curr. Opin. Oncol.？2008, 20, 1–12, doi:10.1097/CCO.0b013e3282f1c595.
[6]
Kwekkeboom, D.J.; de Herder, W.W.; Kam, B.L.; van Eijck, C.H.; van Essen, M.; Kooij, P.P.; Feelders, R.A.; van Aken, M.O.; Krenning, E.P. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: Toxicity, efficacy, and survival. J. Clin. Oncol.？2008, 26, 2124–2130, doi:10.1200/JCO.2007.15.2553.
[7]
Kwekkeboom, D.J.; Teunissen, J.J.; Bakker, W.H.; Kooij, P.P.; de Herder, W.W.; Feelders, R.A.; van Eijck, C.H.; Esser, J.P.; Kam, B.L.; Krenning, E.P. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J. Clin. Oncol.？2005, 23, 2754–2762. 15837990
[8]
Oberg, K.E.; Reubi, J.C.; Kwekkeboom, D.J.; Krenning, E.P. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology？2010, 139, 742–753, doi:10.1053/j.gastro.2010.07.002.
[9]
Pfeifer, A.K.; Gregersen, T.; Gronbaek, H.; Hansen, C.P.; Müller-Brand, J.; Herskind, B.K.; Krogh, K.; Kj？r, A.; Knigge, U. Peptide Receptor Radionuclide Therapy with 90Y-DOTATOC and 177Lu-DOTATOC in Advanced Neuroendocrine Tumors: Results from a Danish Cohort Treated in Switzerland. Neuroendocrinology？2011, 93, 189–196, doi:10.1159/000324096.
[10]
John, M.; Meyerhof, W.; Richter, D.; Waser, B.; Schaer, J.C.; Scherübl, H.; Boese-Landgraf, J.; Neuhaus, P.; Ziske, C.; M？lling, K.; Riecken, E.O.; Reubi, J.C.; Wiedenmann, B. Positive somatostatin receptor scintigraphy correlates with the presence of somatostatin receptor subtype 2. Gut？1996, 38, 33–39, doi:10.1136/gut.38.1.33.
[11]
de Herder, W.W.; Kwekkeboom, D.J.; Feelders, R.A.; van Aken, M.O.; Lamberts, S.W.; van der Lely, A.J.; Krenning, E.P. Somatostatin receptor imaging for neuroendocrine tumors. Pituitary？2006, 9, 243–248, doi:10.1007/s11102-006-0270-5.
[12]
de Jong, M.; Breeman, W.A.; Bernard, B.F.; Bakker, W.H.; Schaar, M.; van Gameren, A.; Bugaj, J.E.; Erion, J.; Schmidt, M.; Srinivasan, A.; Krenning, E.P. [177Lu-DOTA0,Tyr3] octreotate for somatostatin receptor-targeted radionuclide therapy. Int. J. Cancer？2001, 92, 628–633, doi:10.1002/1097-0215(20010601)92:5<628::AID-IJC1244>3.0.CO;2-L.
[13]
Apetoh, L.; Ghiringhelli, F.; Tesniere, A.; Obeid, M.; Ortiz, C.; Criollo, A.; Mignot, G.; Maiuri, M.C.; Ullrich, E.; Saulnier, P.; et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. J.Nat. Med.？2007, 13, 1050–1059, doi:10.1038/nm1622.
[14]
Apetoh, L.; Tesniere, A.; Ghiringhelli, F.; Kroemer, G.; Zitvogel, L. Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res.？2008, 68, 4026–4030, doi:10.1158/0008-5472.CAN-08-0427.
[15]
Lee, Y.; Auh, S.L.; Wang, Y.; Burnette, B.; Wang, Y.; Meng, Y.; Beckett, M.; Sharma, R.; Chin, R.; Tu, T.; et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: Changing strategies for cancer treatment. Blood？2009, 114, 589–595, doi:10.1182/blood-2009-02-206870.
[16]
Caldwell, S.A.; Ryan, M.H.; McDuffie, E.; Abrams, S.I. The Fas/Fas ligand pathway is important for optimal tumor regression in a mouse model of CTL adoptive immunotherapy of experimental CMS4 lung metastases. J. Immunol.？2003, 171, 2402–2412, doi:10.4049/jimmunol.171.5.2402. 12928387
[17]
Ackerman, A.L.; Kyritsis, C.; Tampe, R.; Cresswell, P. Early phagosomes in dendritic cells form a cellular compartment sufficient for cross presentation of exogenous antigens. Proc. Nat. Acad. Sci. USA？2003, 100, 12889–12894, doi:10.1073/pnas.1735556100.
[18]
Burgdorf, S.; Kautz, A.; Bohnert, V.; Knolle, P.A.; Kurts, C. Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science？2007, 316, 612–616, doi:10.1126/science.1137971.
[19]
Pozzi, L.A.; Maciaszek, J.W.; Rock, K.L. Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells. J. Immunol.？2005, 175, 2071–2081, doi:10.4049/jimmunol.175.4.2071. 16081773
[20]
Mukai, T.; Maeda, Y.; Tamura, T.; Matsuoka, M.; Tsukamoto, Y.; Makino, M. Induction of cross-priming of naive CD8+ T lymphocytes by recombinant bacillus Calmette-Guerin that secretes heat shock protein 70-major membrane protein-II fusion protein. J. Immunol.？2009, 183, 6561–6568, doi:10.4049/jimmunol.0803857.
[21]
Oizumi, S.; Strbo, N.; Pahwa, S.; Deyev, V.; Podack, E.R. Molecular and cellular requirements for enhanced antigen cross-presentation to CD8 cytotoxic T lymphocytes. J. Immunol.？2007, 179, 2310–2317, doi:10.4049/jimmunol.179.4.2310. 17675492
[22]
Nagorsen, D.; Voigt, S.; Berg, E.; Stein, H.; Thiel, E.; Loddenkemper, C. Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. J. Transl. Med.？2007, 5, doi:10.1186/1479-5876-5-62.
[23]
Raulet, D.H.; Guerra, N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat. Rev. Immunol.？2009, 9, 568–580, doi:10.1038/nri2604.
[24]
Lee, R.K.; Spielman, J.; Zhao, D.Y.; Olsen, K.J.; Podack, E.R. Perforin, Fas ligand, and tumor necrosis factor are the major cytotoxic molecules used by lymphokine-activated killer cells. J. Immunol.？1996, 157, 1919–1925. 8757310
[25]
Waring, P.; Mullbacher, A. Cell death induced by the Fas/Fas ligand pathway and its role in pathology. Immun. Cell Biol.？1999, 77, 312–317, doi:10.1046/j.1440-1711.1999.00837.x.
[26]
Bossi, G.; Griffiths, G.M. Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells. J. Nat. Med.？1999, 5, 90–96, doi:10.1038/4779.
[27]
Kojima, Y.; Kawasaki-Koyanagi, A.; Sueyoshi, N.; Kanai, A.; Yagita, H.; Okumura, K. Localization of Fas ligand in cytoplasmic granules of CD8+ cytotoxic T lymphocytes and natural killer cells: Participation of Fas ligand in granule exocytosis model of cytotoxicity. Biochem. Biophys. Res. Commun.？2002, 296, 328–336, doi:10.1016/S0006-291X(02)00841-0.
[28]
Ivanov, V.N.; Zhou, H.; Hei, T.K. Sequential treatment by ionizing radiation and sodium arsenite dramatically accelerates TRAIL-mediated apoptosis of human melanoma cells. Cancer Res.？2007, 67, 5397–5407, doi:10.1158/0008-5472.CAN-07-0551.
[29]
Lin, C.C.; Wang, T.E.; Liu, C.Y.; Lin, C.P.; Liu, T.P.; Chen, M.J.; Chang, W.H.; Lin, J.C.; Chang, K.M.; Chu, C.H.; et al. Potentiation of the immunotherapeutic effect of autologous dendritic cells by pretreating hepatocellular carcinoma with low-dose radiation. Clin. Invest. Med.？2008, 31, E150–E159. 18544278
