nach oben

Erschienen in:

01.01.2008 | Original Article

Immunological tumor destruction in a murine melanoma model by targeted LTα independent of secondary lymphoid tissue

verfasst von: David Schrama, Heike Voigt, Andreas O. Eggert, Rong Xiang, He Zhou, Ton N. M. Schumacher, Mads H. Andersen, Per thor Straten, Ralph A. Reisfeld, Jürgen C. Becker

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 1/2008

Einloggen, um Zugang zu erhalten

Abstract

Background

We previously demonstrated that targeting lymphotoxin α (LTα) to the tumor evokes its immunological destruction in a syngeneic B16 melanoma model. Since treatment was associated with the induction of peritumoral tertiary lymphoid tissue, we speculated that the induced immune response was initiated at the tumor site.

Methods and results

In order to directly test this notion, we analyzed the efficacy of tumor targeted LTα in LTα knock-out (LTα^−/−) mice which lack peripheral lymph nodes. To this end, we demonstrate that tumor-targeted LTα mediates the induction of specific T-cell responses even in the absence of secondary lymphoid organs. In addition, this effect is accompanied by the initiation of tertiary lymphoid tissue at the tumor site in which B and T lymphocytes are compartmentalized in defined areas and which harbor expanded numbers of tumor specific T cells as demonstrated by in situ TRP-2/K^b tetramer staining. Mechanistically, targeted LTα therapy seems to induce changes at the tumor site which allows a coordinated interaction of immune competent cells triggering the induction of tertiary lymphoid tissue.

Conclusion

Thus, our data demonstrate that targeted LTα promotes an accelerated immune response by enabling the priming of T cells at the tumor site.

Agyekum S, Church A, Sohail M, Krausz T, Van Noorden S, Polak J, Cohen J (2003) Expression of lymphotoxin-beta (LT-beta) in chronic inflammatory conditions. J Pathol 199:115–121PubMedCrossRef

Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6:205–217PubMedCrossRef

Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252PubMedCrossRef

Bazzoni F, Beutler B (1996) The tumor necrosis factor ligand and receptor families. N Engl J Med 334:1717–1725PubMedCrossRef

Caux C, Vanbervliet B, Massacrier C, Ait-Yahia S, Vaure C, Chemin K, Dieu-Nosjean M, Vicari A (2002) Regulation of dendritic cell recruitment by chemokines. Transplantation 73:S7–S11PubMedCrossRef

Cupedo T, Mebius RE (2005) Cellular interactions in lymph node development. J Immunol 174:21–25PubMed

Cyster JG (1999) Chemokines and cell migration in secondary lymphoid organs. Science 286:2098–2102PubMedCrossRef

Davis IA, Knight KA, Rouse BT (1998) The spleen and organized lymph nodes are not essential for the development of gut-induced mucosal immune responses in lymphotoxin-alpha deficient mice. Clin Immunol Immunopathol 89:150–159PubMedCrossRef

Drayton DL, Liao S, Mounzer RH, Ruddle NH (2006) Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7:344–353PubMedCrossRef

10.

Fan L, Reilly CR, Luo Y, Dorf ME, Lo D (2000) Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol 164:3955–3959PubMed

11.

Finke D (2005) Fate and function of lymphoid tissue inducer cells. Curr Opin Immunol 17:144–150PubMedCrossRef

12.

Fu YX, Chaplin DD (1999) Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 17:399–433PubMedCrossRef

13.

Futterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K (1998) The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9:59–70PubMedCrossRef

14.

Gillies SD, Young D, Lo KM, Foley SF, Reisfeld RA (1991) Expression of genetically engineered immunoconjugates of lymphotoxin and a chimeric anti-ganglioside GD2 antibody. Hybridoma 10:347–356PubMedCrossRef

15.

Gillies SD, Young D, Lo KM, Roberts S (1993) Biological activity and in vivo clearance of antitumor antibody/cytokine fusion proteins. Bioconjug Chem 4:230–235PubMedCrossRef

16.

Haanen JB, Toebes M, Cordaro TA, Wolkers MC, Kruisbeek AM, Schumacher TN (1999) Systemic T cell expansion during localized viral infection. Eur J Immunol 29:1168–1174PubMedCrossRef

17.

Haanen JB, van Oijen MG, Tirion F, Oomen LC, Kruisbeek AM, Vyth-Dreese FA, Schumacher TN (2000) In situ detection of virus- and tumor-specific T-cell immunity. Nat Med 6:1056–1060PubMedCrossRef

18.

Haraguchi M, Yamashiro S, Yamamoto A, Furukawa K, Takamiya K, Lloyd KO, Shiku H (1994) Isolation of GD3 synthase gene by expression cloning of GM3 alpha-2,8- sialyltransferase cDNA using anti-GD2 monoclonal antibody. Proc Natl Acad Sci USA 91:10455–10459PubMedCrossRef

19.

Hjelmstrom P, Fjell J, Nakagawa T, Sacca R, Cuff CA, Ruddle NH (2000) Lymphoid tissue homing chemokines are expressed in chronic inflammation. Am J Pathol 156:1133–1138PubMed

20.

Honda K, Nakano H, Yoshida H, Nishikawa S, Rennert P, Ikuta K, Tamechika M, Yamaguchi K, Fukumoto T, Chiba T, Nishikawa SI (2001) Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer’s patch organogenesis. J Exp Med 193:621–630PubMedCrossRef

21.

Iizuka K, Chaplin DD, Wang Y, Wu Q, Pegg LE, Yokoyama WM, Fu YX (1999) Requirement for membrane lymphotoxin in natural killer cell development. Proc Natl Acad Sci USA 96:6336–6340PubMedCrossRef

22.

Kim HJ, Kammertoens T, Janke M, Schmetzer O, Qin Z, Berek C, Blankenstein T (2004) Establishment of early lymphoid organ infrastructure in transplanted tumors mediated by local production of lymphotoxin alpha and in the combined absence of functional B and T cells. J Immunol 172:4037–4047PubMed

23.

Koni PA, Sacca R, Lawton P, Browning JL, Ruddle NH, Flavell RA (1997) Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 6:491–500PubMedCrossRef

24.

Kratz A, Campos-Neto A, Hanson MS, Ruddle NH (1996) Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J Exp Med 183:1461–1472PubMedCrossRef

25.

Lee BJ, Santee S, Von Gesjen S, Ware CF, Sarawar SR (2000) Lymphotoxin-alpha-deficient mice can clear a productive infection with murine gammaherpesvirus 68 but fail to develop splenomegaly or lymphocytosis. J Virol 74:2786–2792PubMedCrossRef

26.

Lee Y, Chin RK, Christiansen P, Sun Y, Tumanov AV, Wang J, Chervonsky AV, Fu YX (2006) Recruitment and activation of naive T cells in the islets by lymphotoxin beta receptor-dependent tertiary lymphoid structure. Immunity 25:499–509PubMedCrossRef

27.

Lu TT, Cyster JG (2002) Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297:409–412PubMedCrossRef

28.

Lund FE, Partida-Sanchez S, Lee BO, Kusser KL, Hartson L, Hogan RJ, Woodland DL, Randall TD (2002) Lymphotoxin-alpha-deficient mice make delayed, but effective, T and B cell responses to influenza. J Immunol 169:5236–5243PubMed

29.

Luther SA, Bidgol A, Hargreaves DC, Schmidt A, Xu Y, Paniyadi J, Matloubian M, Cyster JG (2002) Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol 169:424–433PubMed

30.

Matsumoto M, Iwamasa K, Rennert PD, Yamada T, Suzuki R, Matsushima A, Okabe M, Fujita S, Yokoyama M (1999) Involvement of distinct cellular compartments in the abnormal lymphoid organogenesis in lymphotoxin-alpha-deficient mice and alymphoplasia (aly) mice defined by the chimeric analysis. J Immunol 163:1584–1591PubMed

31.

Matsushima A, Kaisho T, Rennert PD, Nakano H, Kurosawa K, Uchida D, Takeda K, Akira S, Matsumoto M (2001) Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J Exp Med 193:631–636PubMedCrossRef

32.

Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, Hartson L, Sprague F, Goodrich S, Woodland DL, Lund FE, Randall TD (2004) Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 10:927–934PubMedCrossRef

33.

Muller G, Lipp M (2003) Concerted action of the chemokine and lymphotoxin system in secondary lymphoid-organ development. Curr Opin Immunol 15:217–224PubMedCrossRef

34.

Nasr IW, Reel M, Oberbarnscheidt MH, Mounzer RH, Baddoura FK, Ruddle NH, Lakkis FG (2007) Tertiary lymphoid tissues generate effector and memory T cells that lead to allograft rejection. Am J Transpl 7:1071–1079CrossRef

35.

Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, Cooper MD, Browning JL, Sedgwick JD, Cyster JG (1999) Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J Exp Med 189:403–412PubMedCrossRef

36.

Nishikawa S, Honda K, Vieira P, Yoshida H (2003) Organogenesis of peripheral lymphoid organs. Immunol Rev 195:72–80PubMedCrossRef

37.

Oehen S, Brduscha-Riem K (1998) Differentiation of naive CTL to effector and memory CTL: correlation of effector function with phenotype and cell division. J Immunol 161:5338–5346PubMed

38.

Reisfeld RA, Gillies SD, Mendelsohn J, Varki NM, Becker JC (1996) Involvement of B lymphocytes in the growth inhibition of human pulmonary melanoma metastases in athymic nu/nu mice by an antibody-lymphotoxin fusion protein. Cancer Res 56:1707–1712PubMed

39.

Schrama D, Pedersen LO, Keikavoussi P, Andersen MH, thor Straten P, Brocker EB, Kampgen E, Becker JC (2002) Aggregation of antigen-specific T cells at the inoculation site of mature dendritic cells. J Invest Dermatol 119:1443–1448PubMedCrossRef

40.

Schrama D, Reisfeld RA, Becker JC (2006) Antibody targeted drugs as cancer therapeutics. Nat Rev Drug Discov 5:147–159PubMedCrossRef

41.

Schrama D, thor Straten P, Fischer WH, McLellan AD, Bröcker EB, Reisfeld RA, Becker JC (2001) Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14:111–121PubMedCrossRef

42.

Schrama D, Voigt H, Eggert AO, Xiang R, Reisfeld RA, Becker JC (2005) Therapeutic efficacy of tumor-targeted IL2 in LTalpha(-/-) mice depends on conditioned T cells. Cancer Immunol Immunother 55:861–866PubMedCrossRef

43.

Schrama D, Xiang R, Eggert AO, Andersen MH, Pedersen Ls LO, Kampgen E, Schumacher TN, Reisfeld RR, Becker JC (2004) Shift from systemic to site-specific memory by tumor-targeted IL-2. J Immunol 172:5843–5850PubMed

44.

Suematsu S, Watanabe T (2004) Generation of a synthetic lymphoid tissue-like organoid in mice. Nat Biotechnol 22:1539–1545PubMedCrossRef

45.

Suresh M, Lanier G, Large MK, Whitmire JK, Altman JD, Ruddle NH, Ahmed R (2002) Role of lymphotoxin alpha in T-cell responses during an acute viral infection. J Virol 76:3943–3951PubMedCrossRef

46.

Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O’Fallon WM, Goronzy JJ, Weyand CM (2001) Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167:1072–1080PubMed

47.

thor Straten P, Guldberg P, Seremet T, Reisfeld RA, Zeuthen J, Becker JC (1998) Activation of preexisting T cell clones by targeted interleukin 2 therapy. Proc Natl Acad Sci USA 95:8785–8790CrossRef

48.

Voigt H, Schrama D, Eggert AO, Vetter CS, Muller-Blech K, Reichardt HM, Andersen MH, Becker JC, Luhder F (2006) CD28-mediated costimulation impacts on the differentiation of DC vaccination-induced T cell responses. Clin Exp Immunol 143:93–102PubMedCrossRef

49.

Ware CF (2005) Network communications: lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 23:787–819PubMedCrossRef

50.

Young AC, Zhang W, Sacchettini JC, Nathenson SG (1994) The three-dimensional structure of H-2Db at 2.4 A resolution: implications for antigen-determinant selection. Cell 76:39–50PubMedCrossRef

51.

Yu P, Lee Y, Liu W, Chin RK, Wang J, Wang Y, Schietinger A, Philip M, Schreiber H, Fu YX (2004) Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 5:141–149PubMedCrossRef

Titel: Immunological tumor destruction in a murine melanoma model by targeted LTα independent of secondary lymphoid tissue
verfasst von: David Schrama
Heike Voigt
Andreas O. Eggert
Rong Xiang
He Zhou
Ton N. M. Schumacher
Mads H. Andersen
Per thor Straten
Ralph A. Reisfeld
Jürgen C. Becker
Publikationsdatum: 01.01.2008
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 1/2008
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-007-0352-x

Neu im Fachgebiet Onkologie

CAR-M-Zellen: Warten auf das große Fressen

22.05.2024 Onkologische Immuntherapie Nachrichten

Auch myeloide Immunzellen lassen sich mit chimären Antigenrezeptoren gegen Tumoren ausstatten. Solche CAR-Fresszell-Therapien werden jetzt für solide Tumoren entwickelt. Künftig soll dieser Prozess nicht mehr ex vivo, sondern per mRNA im Körper der Betroffenen erfolgen.

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Immunological tumor destruction in a murine melanoma model by targeted LTα independent of secondary lymphoid tissue