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Y. Zhao
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MO20 - Preclinical Therapeutic Models II (ID 93)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 2
- Moderators:P. Waring, M. Kohonen-Corish
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Gallery B, Level 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)
10:30 - 12:00 | Author(s): Y. Zhao
- Abstract
- Presentation
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.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO20.09 - Systemic blockade of CTLA-4 signaling can improve the abscopal effect induced by local radiotherapy in a murine mesothelioma model (ID 651)
10:30 - 12:00 | Author(s): Y. Zhao
- Abstract
- Presentation
Background
Radiotherapy can induce direct cancer cell death and systemic anti-tumor immunity known as abscopal effect. For malignant pleural mesothelioma (MPM), postoperative hemithoracic radiation is important to control recurrence and metastasis for the resectable patients. We hypothesized that the abscopal effect also exists in malignant mesothelioma, and removal of the immunosuppressive checkpoints was able to enhance this effect induced by local radiotherapy.Methods
Murine malignant mesothelioma AB12 cells were injected subcutaneously into the right leg and flank of Balb/c mice either sequentially (primary/secondary tumors) or concurrently (local/distant tumors). Treatment was initiated on day 5 when primary (local) tumors were developed, and the immune-deficient NOD/SCID mice were used as controls. Local radiotherapy (LRT) with Gammacell-40 Irradiator was delivered to the tumor-bearing leg, whereas the rest of the body was protected with a lead chamber. CTLA-4 blockade with mAb was given 1 day after LRT. Tumor size was measured twice weekly to evaluate the anti-tumor effect. The immune responses, especially T cell activation in tumor, spleen and lymph node was determined by flow Cytometry. The expression of immune-related genes was quantified by RT-PCR, and tumor-infiltrating T cells were determined by immunofluorescent staining.Results
The growth of primary tumors was significantly inhibited by LRT alone, and addition of anti-CTLA-4 mAb enhanced the antitumor effect. Interestingly, the secondary or distant tumors grew more slowly in mice whose primary tumor was treated with LRT than those untreated mice. Some secondary tumors were completely rejected when combined with anti-CTLA4 mAb. There was no such effect on the distant tumors in the immune deficient mice. Results demonstrated that LRT resulted in more T cell infiltration into both primary and secondary tumors. Tumor-infiltrating T cells had higher levels of ICOS and IFN-γ, and proliferated more rapidly after injection of irradiated AB12 cells. More activated CD4 and CD8 T cells were observed in the the draining lymph node (dLn) and spleen, and more dendritic cells trafficked to the dLn. The gene expression of cytolytic enzymes and cytokines was upregulated as well.Conclusion
LRT on primary tumors has abscopal effect on the secondary or distant tumor, and this effect can be enhanced by systemic blockade of CTLA-4 in murine mesothelioma. This approach might be translated into clinical trials for MPM patients.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
