Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses.
OBJECTIVE
Electrochemotherapy (ECT) is an effective local therapy of human cutaneous cancers but has no effect on distant untreated tumors. We addressed whether tumor-associated antigens released after ECT could induce an efficient systemic immunity when associated with an appropriate immunoadjuvant.


RESULTS
We first studied the nature of the cellular recruitment and the expression of various toll-like receptors (TLRs) in tumors treated by ECT. We found that ECT induced a massive recruitment of CD11c and CD11b positive cells in the tumors and a strong increase of TLR9 expression. We then tested antitumor effects of the combination: ECT followed by TLR-9 ligands, CpG oligodeoxynucleotides (CpG ODN), in three murine tumor models. We found that this combination triggered both potent local synergistic antitumor effects, on the ipsi-lateral ECT-treated tumor, and more interestingly, a systemic antitumor response on the contra-lateral untreated tumor, in the three models. The systemic protection was T-cell dependent as it was not observed in nude littermates. The combination induced tumor-specific T cell effectors in the tumor-draining lymph nodes and in the spleen which secreted significantly more gamma-interferon upon activation than with ECT or CpG ODN alone.


CONCLUSIONS
Our data show that ECT and CpG ODN synergize and induce a significant increase of the local effect and a systemic T-dependent antitumor response. Such combination constitutes a potential innovative vaccination strategy using in situ tumor-associated antigens that could eventually be translated into the clinic.
Roux
Stephan
S
INSERM U805, Villejuif, France. sroux@igr.fr
Bernat
Claire
C
Al-Sakere
Bassim
B
Ghiringhelli
François
F
Opolon
Paule
P
Carpentier
Antoine F
AF
Zitvogel
Laurence
L
Mir
Lluis M
LM
Robert
Caroline
C
D000276:Adjuvants, Immunologic; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D039481:CD11b Antigen / Q000096:biosynthesis; D039521:CD11c Antigen / Q000096:biosynthesis; D018899:CpG Islands; D053672:Electrochemotherapy / Q000379:methods*; D005260:Female; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D009841:Oligonucleotides / Q000737:chemistry; D051217:Toll-Like Receptor 9 / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D039481:CD11b Antigen; D039521:CD11c Antigen; D009841:Oligonucleotides; D051217:Toll-Like Receptor 9