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Z. Yun



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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.08 - Activation of CD1d-restricted NKT cells may inhibit cancer cell repopulation between cycles of chemotherapy through modulating immune responses in murine mesothelioma (ID 650)

      11:15 - 11:20  |  Author(s): Z. Yun

      • Abstract
      • Presentation
      • Slides

      Background
      Considerable evidence has shown that cancer cell repopulation during the intervals of chemotherapy is a neglected factor of treatment failure. The efficacy of cancer treatment may be improved if this process could be effectively controlled. It has been demonstrated that the number of invariant natural killer T cells (iNKT) increased during the development of murine mesothelioma models. NKT cells specifically recognize the glycolipid α-galactosylceramide (KRN7000, KRN) through CD1d molecule resulting in their activation and expansion. Our goal is to study the impact of NKT cell activation by KRN on cancer cell repopulation between cycles of chemotherapy in murine mesothelioma model.

      Methods
      Tumor-bearing mice were treated with chemotherapy once weekly, and KRN was followed after each cycle of chemotherapy. Both WT and CD1dKO mice were used to evaluate the effect on tumor growth. Cancer cell proliferation and apoptosis was evaluated by Ki67 and TUNEL immunohistochemistry, respectively. The proportion of CD4[+] and CD8[+] T cells and their activation in the tumor, spleen, draining lymph node and peripheral blood from tumor-bearing mice were determined by using flow cytometry, and gene expression of activated T cell-related cytokines and cytolytic enzymes were quantified by RT-PCR. NKT were recognized specifically by CD1d-tetramer staining.

      Results
      In WT mice, tumor growth delay was achieved by chemotherapy alone, and this effect was improved when combined with KRN. Cancer cell repopulation between cycles of chemotherapy was significantly inhibited by KRN, whereas apoptosis changed inversely. KRN following chemotherapy resulted in an increase of IFN-γ production in the draining lymph node, blood and spleen. Strikingly, the percentage of ICOS+CD4 T cells, Th17 and Tc17 cells increased in splenocytes. NKT expansion was observed in both peripheral blood and lymphoid organs. Gene expression of immune-associated cytokines was somewhat upregulated after NKT cell activation during the intervals of chemotherapy. In KO mice, however, Cis alone or Cis+KRN was less effective than in WT mice. KRN alone had little effect in both animals.

      Conclusion
      NKT activation between cycles of chemotherapy can improve the efficacy of treatment through modulating anti-tumor immunity against cancer cell repopulation. KRN may be a promising agent for mesothelioma immunotherapy.

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