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J.C. Steel



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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.07 - Lung Cancer-Initiating Cells Avoid Immune Recognition (ID 3314)

      11:05 - 11:10  |  Author(s): J.C. Steel

      • Abstract
      • Presentation
      • Slides

      Background
      Increasing evidence supports the concept of a unique population of cells within a tumor with stem cell-like characteristics. These cancer-initiating cells (CICs) are thought to be responsible for tumor organization, maintenance, progression and recurrence, as well as contributing to radiation and chemotherapy resistance. In this study we outline a new characteristic of CICs, one in which the CIC can subvert the host immune response. We pose that this characteristic is essential for the establishment of a tumor in an immunocompetent host and may represent a mechanism in which lung tumors may gain resistance to immune based therapies.

      Methods
      We examined whether lung CICs could be enriched from murine and human cell lines through the use of tumorsphere culture assays. We vaccinated mice against the HPV E7 antigen and challenged mice with HPV E6/7 expressing murine lung cancer cells (TC-1) enriched for CICs. We also examined ex-vivo the capacity of CD8 and NK cells derived from vaccinated mice to lyse CICs. We examined by flow cytometry the expression of MHC-I and NK activating ligands. We examined the effect of interferon gamma (IFN-γ) on MHC-I expression by CICs and determined whether increased MHC-I by CICs would inhibit tumor formation in an immunocompetent animal.

      Results
      We showed that both murine and human lung cancer cells can be grown and maintained in tumorsphere culture conditions. The resulting cells were enriched for CICs as evidenced by increased OCT4, NANOG, and/or SOX2 expression. Additionally, tumorsphere cultures of murine tumor lines had increased tumor take in immunocompetent animals, however this was significantly less than that seen in immunodeficient mice; indicating that true CICs must be able to thwart the immune response to establish tumors. In order to further examine this, we vaccinated mice with HPV E7 peptides and challenged with TC-1 non-CICs or CICs. We showed that mice challenged with CICs had no survival advantage compared to non-vaccinated animals; whereas those animals challenged with non-CICs exhibited a vaccine induced survival advantage. Further we showed ex-vivo that CICs were resistant to lysis from CD8+ T-cells compared to the non-CICs. Next, we showed that both murine and human lung CICs have down-regulated expression of MHC-I as well as a number of ligands for NK cell activating receptors, essentially making them “opaque” to the immune system and therefore less susceptible to CTL or NK cell lysis. Further, we demonstrate that IFN-γ increases MHC-I expression on CICs and restores sensitivity to CTL killing. Finally, we demonstrate that decreased MHC-I expression is a critical component of the ability of CICs to establish tumor in immunocompetent hosts.

      Conclusion
      Increasing evidence indicates that CICs are critical players in the development and establishment of cancers. In this study we demonstrated that these cells also subvert tumor immune surveillance and play a key role in the resistance of tumors to cancer vaccines through their ability to escape host immune responses. Our results demonstrated that modulation of MHC-I on CICs can alter their susceptibility to T-cell mediated lysis thus opening a new target for cancer vaccine strategies.

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    P3.04 - Poster Session 3 - Tumor Immunology (ID 155)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.04-004 - Interleukin-15: A potential factor in establishment and progression of lung cancer (ID 3393)

      09:30 - 09:30  |  Author(s): J.C. Steel

      • Abstract

      Background
      Interleukin-15 (IL-15) is a potent pro-inflammatory cytokine, that plays a major role in stimulating immune effector cells following microbial and viral infection. IL-15 exhibits broad activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells. IL-15 is primarily expressed by antigen presenting cells; however, in areas where there are high microbial loads, such as the lungs and colon, epithelial cells may also express IL-15 and its receptor (IL-15Rα). The expression of IL-15 and IL-15Rα by the lung epithelium facilitates immune responses by inducing local proliferation of NK and CD8+ T-cells in response to infection. Here we determine the status of IL-15 and IL-15Rα on lung cancers and assess their ability to stimulate the proliferation of these immune cells.

      Methods
      Western blotting, ELISA and qPCR were used to determine the expression of IL-15 and IL-15Rα in 6 human lung cancer cell lines and 1 normal human bronchial epithelial cell (HBEC) line. Further, mRNA from 146 primary lung cancers of all stages and tissues from 45 normal lungs were examined by multiplex qPCR for the expression of IL-15 and IL-15Rα. NK and T-cell proliferation assays were performed to determine the effects of IL-15 expression by the cell lines on these immune cells.

      Results
      IL-15 expression by lung cancer cell lines was significantly reduced compared to the HBEC cell line. Similar results were seen when we examined the expression of IL-15 in primary tumors, with lung cancer expressing less IL-15 than normal lung (P<0.001). When we compared IL-15 expression between stages, we found that increased stage correlated with a decrease in IL-15 expression with normal lung> stage I> stage II> stage III> stage IV. In contrast, IL-15Rα expression levels in the tumor samples were found to be largely unchanged across stage, P=0.417. Decreases in IL-15 with increasing stage may represent one mechanism in which lung cancers limit the immune response directed at the tumor and may aid in metastatic progression. In order to assess the immune effects of a reduction in IL-15 expression, we examined the ability of the lung cancer cell lines and HBEC to induce the proliferation of NK and T-cells following co-incubation. We found that the lung cancer cell lines significantly inhibited the proliferation of either NK or T-cells compared to HBEC.

      Conclusion
      Pro-inflammatory cytokines such as IL-15 are important for the induction of lung immunity. Decreases in IL-15 expression may reduce immune responses thereby aiding in the escape of lung cancer from immune detection and the dissemination of tumor. The differential expression of IL-15 across lung cancer stages and retention of IL-15Rα expression may make lung cancer a target for IL-15-based treatments and opens the potential for IL-15 to be used as a predictive biomarker in early stage patients.