Author of

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  P2.04 - Poster Session 2 - Tumor Immunology (ID 154)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11514

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    P2.04-003 - Novel mechanism of immune-tolerance due to aberrant expression of Natural Killer-Cell Immunoglobulin-like Receptors (KIRs) and enhanced platelet interactions (ID 3389)

    11:30 - 12:30  |  Author(s): T.T. Chan
    • Abstract

    Background
    Cancer metastasis is the main cause of cancer-related deaths. Metastatic cancer cells spread through blood vessels where they constantly interact with platelets and leukocytes, forming tumor microemboli and thereby protected from otherwise rapid elimination from host immune defense cells such as NK cells. Platelets are known to be prometastatic and pro-angiogenic. They release platelet-derived growth factors, chemokines, various adhesion molecules and coagulation factors that effectively promote cancer spreading and metastasis. We previously demonstrated that many metastatic cancer cells acquire immune-resistance by aberrant expression of KIRs on their surface. We showed that cancer cells with aberrant expression or with forced ectopic expression of KIRs are more resistant to NK killing than those with null or low KIR expression. Pre-blocking with anti-KIR antibodies effectively reverses their sensitivity to NK killing. Here we report that KIR-expressing cancer cells interact strongly with platelets leading to increase NK tolerance compared to cancer cells with null or low KIR expression. These data support a novel mechanism of immune-tolerance due to aberrant KIR expression on metastatic cancer cells.

    Methods
    DNA microarrays were performed on metastatic lung cancer cells re-derived from orthotopic human metastatic lung tumors in athymic nude rats. Aberrant expression of KIR genes was detected and verified with immunohistochemistry and flow cytometry. For ectopic expression, lung adenocarcinoma parental cells (H2122-GFP) were transfected with KIR2DL1 (LL454) and/or KIR3DL1 (LL456) plasmids. Stable transformants were enriched by cell sorting. Binding of these cancer cells with differential KIR expression with human platelets, pre-labeled with anti-CD41-APC antibodies, were analyzed by flow cytometry. NK killing of GFP-tagged cancer cells with differential KIR expressions in the presence and absence of human platelets was accessed with fluorescence intensity in a fluorescent plate reader.

    Results
    Using in vitro cytotoxic assays, we found that KIR expression or platelet coating on cancers clearly increased their resistance to NK cell killing when compared with parental cells. Interestingly, we found that platelet coating on those metastatic cancer cells with high aberrant KIR expression increased their IC50 values by 6 to 14 folds respectively when compared with parental cells, while platelet coating on those cells with forced KIR expression also increased their IC50 values by 9 to 12 folds respectively. Our observation shows that NK tolerance correlates positively with platelet coating and the levels of KIR expression on the cancer cells (with correlation coefficient = 0.9 to 0.98), and that the NK resistance is the highest when both KIR aberrant expression and platelet coating are present on the cancer cells.

    Conclusion
    We discovered a novel mechanism of immune resistance to NK cells due to aberrant expression of KIRs on cancer cells. Aberrant KIR expression on cancer cells enhanced their interaction with platelets leading to further increase in NK tolerance than those cells with null or low KIR expression. This observation suggests that anti-platelet antagonists and anti-KIR antibodies may have clinical potential for the treatment or prevention of metastatic and immune resistant cells.