Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer.
OBJECTIVE
Hepatocellular carcinoma (HCC) often lacks curative treatment; therefore new efficient therapies are needed. In this work we aimed at evaluating the antitumor effect of interleukin-12 (IL-12)-based gene therapy on HCC occurring spontaneously in mice.


METHODS
A plasmid-vector expressing IL-12 in a liver-specific and doxycycline (Dox)-inducible manner was transferred by hydrodynamic injection to the liver of L-PK/c-myc mice with HCC. IL-12 expression was induced by administering Dox (3 cycles of 1 month duration separated by 1 month rest).


RESULTS
Dox administration increased serum IL-12 and IFN-gamma and induced tumor lymphocytic infiltration in all treated mice which was accompanied by tumor stabilization or regression in 40% of animals. The antitumor effect did not correlate with levels of IL-12 or IFN-gamma nor with the intensity of tumor mononuclear infiltration. However, tumors from non-responder mice showed more abundance of Foxp3+ regulatory T cells and higher expression of the immunosuppressive molecules PD-1, PD-L1, VEGF, CTLA-4, IDO, and IL-10 than those that responded to therapy.


CONCLUSIONS
Although long-term induction of IL-12 expression in the liver can inhibit HCC growth, the efficacy of the treatment appears to be limited by the activation of immunosuppressive mechanisms.
Zabala
Maider
M
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), Spain.
Lasarte
Juan José
JJ
Perret
Christine
C
Sola
Josu
J
Berraondo
Pedro
P
Alfaro
Maite
M
Larrea
Esther
E
Prieto
Jesús
J
Kramer
M Gabriela
MG
D000818:Animals; D002634:Chemotaxis, Leukocyte; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D007155:Immunologic Factors / Q000235:genetics; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000097:blood; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy*; D008214:Lymphocytes; D051379:Mice; D008822:Mice, Transgenic; D010957:Plasmids; D050378:T-Lymphocytes, Regulatory; D016896:Treatment Outcome; D047368:Tumor Burden
D007155:Immunologic Factors; D018664:Interleukin-12; D007371:Interferon-gamma; D004318:Doxycycline