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N. Ahn
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ORAL 41 - Immune Biology, Microenvironment and Novel Targets (ID 159)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.K. Padda, R. Nemenoff
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F1+F2
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ORAL41.02 - Novel Mechanism of Immune-Tolerance and Cancer Metastasis Due to Aberrant Expression of Natural Killer Immunoglobulin-Like Receptors (KIRs) (ID 2199)
18:41 - 18:52 | Author(s): N. Ahn
- Abstract
- Presentation
Background:
Natural Killer (NK) cells are a major defense to eliminate cancer cells. Cancer cells and metastases may have aberrantly expressed KIRs to prevent killing by NK cells. In addition, platelets may inhibit NK killing of cancer cells. Metastatic cancer cells spread through blood vessels where they constantly interact with platelets by forming tumor microemboli and thereby protected from otherwise rapid elimination from host immune defense cells such as NK cells. Here, using an in vivo model of cancer metastasis in athymic nude mice by directly injecting cancer cells into the blood stream, we study the ability of platelets and KIRs in helping cancer cells to escape from immune surveillance and promote metastasis.
Methods:
GFP-luciferase tagged human lung adenocarcinoma cell line, H2122-GL, was further transfected with KIR2DL1 (LL454) plasmids. Stable transformants were enriched by cell sorting. In vivo experimental metastasis were performed in both athymic nude mice and in Nbeal2 knockout and wild type C57 black mice, by tail vein injections of H2122 parental and KIR expressing cells, with and without pre-infusion of human platelets. Levels of tumor cells detected in the lung and other sites were closely monitored by bioluminescence imaging at various time intervals, using an IVIS200 imager.
Results:
24 hours after tail vein injection of a million parental H2122-GL, as low as 0.4 million photons were detectable in the lungs of nude mice (n=5), while those mice injected with a same number of H2122-GL-KIR2DL1 cells, they produced 1.85 million photons in the lungs, showing a 4.6 fold increase in accumulation of KIR-expressed cancer cells than those parental cells in the lung. When the nude mice were pre-infused with iv injection of human platelets followed by tail vein injection of parental or KIR-expressed H2122 cells, enhancement up to 7 fold of lung metastases of KIR expressed H2122 were detected relative to the parental cells as early as 24 hours. 5 weeks post injection, an enhancement up to 190 fold in bioluminescence intensity was found with KIR expressed cells relative to the parental cells. Interestingly, the enhancement of lung metastases was abrogated when similar experiments were repeated in the NBeal2 knockout mice, whose platelets were nonfunctional due to defective alpha-granules and deficiency in their cargo, including von Willebrand factor, thrombospondin-1, and platelet factor 4. One hour after tail vein injection, both parental and KIR expressed H2122 cells produced same but low number of lung metastases, indicating that the defective platelets in the ko mice had failed to promote lung metastases. In the wild type mice, significantly more KIR expressed H2122 cells were detected in the lung relative to parental cells. However, as expected, these early lung metastases were rejected later by the host intact immune cells.
Conclusion:
Our studies demonstrated that metastatic cancer cells acquire immune-resistance by aberrantly express Natural Killer-Cell Immunoglobulin-like Receptors (KIRs) on their surface and that KIR-expressing cancer cells interact more strongly with platelets leading to significantly increase in NK tolerance and enhancing cancer metastases in pre-clinical models.
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