Immunological tumor destruction in a murine melanoma model by targeted LTalpha independent of secondary lymphoid tissue.
BACKGROUND
We previously demonstrated that targeting lymphotoxin alpha (LTalpha) 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.


RESULTS
In order to directly test this notion, we analyzed the efficacy of tumor targeted LTalpha in LTalpha knock-out (LTalpha(-/-)) mice which lack peripheral lymph nodes. To this end, we demonstrate that tumor-targeted LTalpha 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 LTalpha 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.


CONCLUSIONS
Thus, our data demonstrate that targeted LTalpha promotes an accelerated immune response by enabling the priming of T cells at the tumor site.
Schrama
David
D
Department of Dermatology, Julius-Maximilians-University, University of Würzburg, Josef-Schneider-Str. 2, Buildg. D8, 97080, Würzburg, Germany. Schrama_D@klinik.uni-wuerzburg.de
Voigt
Heike
H
Eggert
Andreas O
AO
Xiang
Rong
R
Zhou
He
H
Schumacher
Ton N M
TN
Andersen
Mads H
MH
thor Straten
Per
P
Reisfeld
Ralph A
RA
Becker
Jürgen C
JC
D000818:Animals; D005732:Gangliosides / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology*; D008233:Lymphotoxin-alpha / Q000276:immunology* / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology
D005732:Gangliosides; D008233:Lymphotoxin-alpha; D011993:Recombinant Fusion Proteins; C025447:sialogangliosides