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

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 MIP3a (Ad-CMVIL-12+AdCMVMIP3a) 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-3a. Importantly, relapsing cell lines were insensitive to in vitro induction of apoptosis by IFNg, 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 IFNg.

Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations

“…The complex genetic changes leading to acquired resistance to PD-1 blockade, wherein one JAK1/2 allele was mutated and amplified and the other was lost, suggest a strong selective pressure induced by the therapeutic immune response. Similar events leading to lack of sensitivity to interferon gamma have been reported in the cancer immune-editing process and acquired resistance to immunotherapy in mouse models (15–17) and in patients treated with the anti-CTLA-4 antibody ipilimumab who did not respond to therapy (18). Therefore, lack of interferon gamma responsiveness allows cancer cells to escape from antitumor T cells, and in the context of anti-PD-1/L1 therapy, results in the loss of PD-L1 expression, the target of PD-1 blockade therapy, which would abrogate the antitumor efficacy of this approach.…”

CD4+/CD25+ Regulatory Cells Inhibit Activation of Tumor-Primed CD4+ T Cells with IFN-γ-Dependent Antiangiogenic Activity, as well as Long-Lasting Tumor Immunity Elicited by Peptide Vaccination

“…Because IFN-␥ has multiple biological activities, and its receptor (IFN-␥R) is expressed in almost all cell types (39,40), this cytokine might have direct effects on tumor cells such as: 1) inhibiting cell proliferation or sensitizing cells to apoptosis (41,42); 2) up-regulating MHC class I expression and thereby increasing tumor cell lysis (43); 3) up-regulating MHC class II expression on tumor cells (44,45), 4) stimulating NK activity (46), or 5) inducing the expression of angiogenesis inhibitors, like IFN-␥-inducible protein-10, by tumor and stromal cells (47). We have not found any inhibitory effect of IFN-␥ on proliferation of CT26 tumor cells in vitro even at doses of 7500 U/ml (around 3 ϫ 10 6 pg/ml) (not shown).…”

Intratumoural administration of dendritic cells: hostile environment and help by gene therapy

“…The authors detected an infiltrate of CD11c cells in the tumour and also in draining lymph nodes, which became enlarged. In a subsequent study [132], also with an adenovirus encoding MIP-3α, it was found that it was synergistic with gene transduction of the tumour with IL-12 by means of recombinant adenovirus, achieving complete regressions in CT26 and the experimental pancreatic carcinoma PANC02. In both studies, the antitumour effect was dependent on T cells and correlated with CTL responses.…”