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Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNγ-induced apoptosis

Gene Therapy volume 10, pages 1067–1078 (2003)Cite this article

Abstract

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 MIP3α (AdCMVIL-12+AdCMVMIP3α) 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-3α. Importantly, relapsing cell lines were insensitive to in vitro induction of apoptosis by IFNγ, 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 IFNγ.

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Acknowledgements

We thank Dr Bendandi and Tirapu for critical reading and helpful discussion. Juan Percaz, Javier Guillen, Izaskun Gabari and Celia Gomar are acknowledged for their technical assistance. The team at Medplant Genetics is acknowledged for assistance with the microarray technology. Financial support was from CICYT (SAF 99/0039), Gobierno de Navarra and grants from Fundación Ramón Areces and Inés Bemberg.

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Authors and Affiliations

  1. Department of Medicine, Gene Therapy Unit, School of Medicine, University of Navarra, Pamplona, Spain

    G Mazzolini, I Narvaiza, L A Martinez-Cruz, A Arina, M Barajas, J C Galofré, C Qian, J M Mato, J Prieto & I Melero

  2. Department of Medicine, Genomic and Proteomic Unit, School of Medicine, University of Navarra, Pamplona, Spain

    L A Martinez-Cruz & J M Mato

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Mazzolini, G., Narvaiza, I., Martinez-Cruz, L. et al. Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNγ-induced apoptosis. Gene Ther 10, 1067–1078 (2003). https://doi.org/10.1038/sj.gt.3301957

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