Abstract #1147: Roles of natural killer-cell immunoglobulin-like receptors (KIR) in immune escape and cancer metastasis

Abstract

Background: The aim of this study is to investigate the mechanism of immune-escape and cancer metastasis through an aberrant expression of the natural killer (NK) cell immunoglobulin-like receptors (KIRs) on human lung cancer cells. The concept of immune-editing suggests that the immune system not only protects the host against development of primary nonviral cancer but also sculpts tumor immunogenicity for increasingly aggressive growth and further resistance to immune destruction as they progress. In this report, we provide evidence supporting and expanding the concept of immune-editing and immune escape leading to the development of metastases. Methods: Human lung cancer cell line H2122 was tagged with green fluorescent protein (GFP) and in vivo imaging was used to track metastasis in an orthotopic lung model in athymic nude rats. Primary tumors and distant metastases were aseptically isolated and grew in tissue culture. RNAs were extracted for gene profiling using Affymetrix Hu-133 plus 2 and were analyzed with the GeneSpring. Expression of proteins was verified with antibodies using flow cytometry. Results: We have detected that a whole family of human KIR receptors were aberrantly expressed on the surface of H2122 cancer cells after orthotopic implantation in nude rats. KIR expression levels increase progressively in metastases in direct relationship to their distance from the primary tumor, and correlates strongly with metastatic behavior. In contrast, KIR was barely detectable in the parental cell line in vitro. Interestingly, except for KIR genes, other NK cell markers were barely detectable and they failed to change progressively from primary to metastatic cancer cells. KIR expression was also up-regulated in metastases isolated from other non-small cell lung cancer cell lines A549 and H157 after orthotopic implantation in the lungs of nude rats or in metastases from Mia-PaCa pancreatic tumor after implanted orthotopically in the pancreas of nude mice. Using anti-proliferative assays, we have demonstrated that lung metastases with high KIR expression are more resistant than parental cells to cytolytic killing by human or rodent NK cells in vitro. Furthermore, continuous co-culture of parental lung cancer cells with cytolytic human or rodent NK cells results in the selection of resistant cancer cell subpopulations with significantly elevated expression of surface KIRs that are immuno-resistant. Conclusions: We conclude that exposure of human cancer cells to NK cells either in vitro or in vivo results in the selection of immuno-resistant cancers due to elevated expressions of KIR on their surfaces. We hypothesize that cancer metastases with elevated KIR expression levels acquire features that can fool the immune system into thinking of the cancer as \#8220;self\#8221; that allows them to escape immuno-surveillance and metastasize to distant organs.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1147.