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Tumor Cell Repopulation between Cycles of Chemotherapy is Inhibited by Regulatory T- Cell Depletion in a Murine Mesothelioma Model  Licun Wu, MD, Zhihong.

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Presentation on theme: "Tumor Cell Repopulation between Cycles of Chemotherapy is Inhibited by Regulatory T- Cell Depletion in a Murine Mesothelioma Model  Licun Wu, MD, Zhihong."— Presentation transcript:

1 Tumor Cell Repopulation between Cycles of Chemotherapy is Inhibited by Regulatory T- Cell Depletion in a Murine Mesothelioma Model  Licun Wu, MD, Zhihong Yun, MSc, Tetsuzo Tagawa, MD, PhD, Katrina Rey-McIntyre, BSc, Masaki Anraku, MD, MSc, Marc de Perrot, MD, MSc  Journal of Thoracic Oncology  Volume 6, Issue 9, Pages (September 2011) DOI: /JTO.0b013e ee0 Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 Murine mesothelioma AC29 cells were injected subcutaneously (SC) into the flanks of CBA mice. Once tumors are palpable (approximately 5 mm in diameter at day 4 ± 1 posttumor cell injection), treatment was initiated as follows: no treatment, cisplatin (Cis) alone, cyclophosphamide alone, PC61 alone, cisplatin combined with Treg depletion by CD25 monoclonal antibody PC61 (CPC), or cisplatin combined with low dose of cyclophosphamide (CCY) (A). Tumor growth delay after both combination treatments with PC61 or CY following cisplatin was achieved (B and C). Each group contained at least five mice. Tumor growth curves after treatment shown are the averages of three experiments. *p < 0.05, compared with controls. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e ee0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Tumor cell repopulation between cycles of chemotherapy was inhibited by Treg cell depletion with anti-CD25 monoclonal antibody PC61. Single tumor cells were prepared at day 21 after treatment. BrdU was injected intraperitoneally (IP) 3 hours before animals were killed. BrdU labeling index of tumor cells was determined by flow cytometry. Representative data generated from five tumors of each group on day 21 showing tumor cell repopulation (A). Nuclear immunostaining of BrdU incorporation and quantification of highlighted positive nuclear areas were shown in (B) and (C), respectively. Gene expression of internal proliferation markerKi67 was evaluated by real-time reverse-transcribed polymerase chain reaction (RT-PCR) (D). Columns, mean; bars, SEM. *p < 0.05, compared with controls. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e ee0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Populations of T-cell subsets 7 days after completing three cycles of chemotherapy. Single cells from the spleen, draining lymph node, and peripheral blood were prepared and stained according to the methods mentioned earlier in the text. Treg cells were identified by positive staining of CD4+CD25+FoxP3+. The proportion of Treg cells was analyzed based on positivity of the above three markers, and all p values are less than 0.05 in the CPC group (A). Total CD4+ T cells and CD8+ T cells were determined by the proportion of CD3+CD4+ and CD3+CD8+ cells by flow cytometry, and there was no significant difference as shown in (B). Each group had at least five mice, and the experiment was repeated twice. Columns, mean; bars, SEM. *p < 0.05, compared with controls. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e ee0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

5 FIGURE 4 Populations of T-cell subsets 7 days after completing three cycles of chemotherapy. Single cells from the tumor tissues were prepared and stained according to the methods. Treg cells were identified by positive staining of CD4+CD25+, CD4+FoxP3+, and CD4+CD25+FoxP3+. The proportion of Treg cells was analyzed based on positivity of the above three markers (A). Total CD4+ T cells and CD8+ T cells were determined by the proportion of CD3+CD4+ and CD3+CD8+ cells by flow cytometry (B). (Each group had at least five mice, and the experiment was repeated twice). Columns, mean; bars, SEM. *p < 0.05, compared with controls. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e ee0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

6 FIGURE 5 Specific cell killing of splenocytes derived from AC29 tumor-bearing mice treated with cisplatin (Cis) or PC61 alone, combination of cisplatin with PC61 (CPC) or cyclophosphamide (CCY), and naive mice were also included as control. This experiment was repeated at least twice. *p < 0.05, compared with naive mice. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e ee0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

7 FIGURE 6 Cytokine production in tumor tissue 7 days after completing treatment by enzyme-linked immunosorbent assay (ELISA) (top panel, A), and gene expression of activated T-cell-related cytokines was shown in reverse-transcribed polymerase chain reaction (RT-PCR) results (bottom panel, B). All these experiments were repeated twice. Columns, mean; bars, SEM. *p < 0.05, compared with controls. Journal of Thoracic Oncology 2011 6, DOI: ( /JTO.0b013e ee0) Copyright © 2011 International Association for the Study of Lung Cancer Terms and Conditions

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