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| Vascular Endothelium Contributes to Tumor Tolerance Induction |
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Ruben G. Nava, Sanjay Murala, Alec Patterson, Andrew Gelman, Daniel Kreisel, Sasha A. Krupnick; Surgery, Washington University in St Louis, St Louis, MO Objective: Tumor vasculature is critical for malignant progression but has been considered mainly supportive in nature, providing nutrients and eliminating waist products in the tumor microenvironment. Our laboratory has recently described that antigen presentation by murine vascular endothelium can result in the generation of CD4+FoxP3+ regulatory T cells. This created the possibility that presentation of tumor associated antigen by vascular endothelium in vivo may contribute to tumor tolerance. Methods: In order to study this possibility we took advantage of a recently described model of orthotopic left single lung transplantation. This model is ideal for such studies since within several days of transplantation the donor derived hematopoietic cells are replaced by those of the recipient while all non-hematopoietic cells, such as vascular endothelium, remain of donor origin. Thus transplantation of a B6 MHC II- donor to a B6 wild-type recipient could be used to create a "chimeric organ" consisting of MHC II deficient vascular endothelial cells repopulated by wild-type hematopoietic cells. Such an experimental system results in the local disruption of CD4+ T cell-restricted antigen presentation by vascular endothelial cells in the lung. As the native right lung of the recipient remains unaffected it can thus act as an internal control in the same animal. We thus transplanted left B6 MHCII- or wild-type B6 lungs into a B6 recipients and injected B16 melanoma intravenously 1 week after transplantation. Results: Three weeks after tumor injection the lung tumor burden was calculated by weight and visual inspection. While the transplanted B6 lung supported significant growth of tumor (127.9±41 mg), little tumor growth was detected in the transplanted MHCII- lung (13±7.7 mg). Identical tumor growth was detectable in the native right lungs of both groups of recipients (165±30 vs. 172±57 mg). Evaluation of tumor infiltrating T cells demonstrated an increase in both CD4+ and CD8+ T cells with higher level of T cell activation, measured by CD69 expression, in lungs deficient in non-hematopoietic MHC II. Conclusion: Based on our preliminary data we can conclude that expression of MHC Class II in the tumor microenvironment by vascular endothelium and other non-hematopoietic cells may be critical to T cell homeostasis and may play a role in the induction of tumor tolerance. Such mechanisms may need to be taken into account when combining anti-angiogenesis and immune based therapy. Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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