Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNgamma-induced apoptosis.
Combined injections into experimental tumor nodules of adenovirus encoding IL-12 and certain chemokines are capable to induce immune-mediated complete regressions. In this study, we found that the combination of two adenoviruses, one encoding IL-12 and other MIP3alpha (AdCMVIL-12+AdCMVMIP3alpha) was very successful in treating CT-26-derived colon carcinomas. However, in experimental tumors generated from the pancreatic carcinoma cell line Panc02 such combined treatment induces 50% of macroscopic complete regressions, although local relapses within 1 week are almost constant. We derived cell lines from such relapsing tumors and found that experimental malignancies derived from their inoculum were not amenable to treatment in any case with AdCMVIL-12+AdCMVMIP-3alpha. Importantly, relapsing cell lines were insensitive to in vitro induction of apoptosis by IFNgamma, in clear contrast with the original Panc02 cells. Comparative analyses by cDNA arrays of relapsing cell lines versus wild-type Panc02 were performed revealing an important number of genes (383) whose expression levels were modified more than two-fold. These changes grouped in certain gene ontology categories should harbor the mechanistic explanations of the acquired selective resistance to IFNgamma.
Mazzolini
G
G
Gene Therapy Unit, Department of Medicine, School of Medicine, University of Navarra, Avda. Pio XII s/n, 31008 Pamplona, Spain.
Narvaiza
I
I
Martinez-Cruz
L A
LA
Arina
A
A
Barajas
M
M
Galofré
J C
JC
Qian
C
C
Mato
J M
JM
Prieto
J
J
Melero
I
I
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000235:genetics; D003110:Colonic Neoplasms / Q000628:therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000627:therapeutic use; D018664:Interleukin-12 / Q000235:genetics; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D017471:Receptors, Interferon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000235:genetics*
C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D017471:Receptors, Interferon; D018664:Interleukin-12; D007371:Interferon-gamma