Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes.
Transgenic mice expressing the oncogene SV40 T antigen (Tag) in the insulin-producing beta cells of the pancreas develop islet cell carcinomas. Expression of the oncogene beginning in adult life leads to autoimmunity and lymphocytic infiltration of premalignant lesions. Nevertheless, Tag-expressing solid tumors escape the immune surveillance and are devoid of infiltrating lymphocytes. Attempting to elicit a tumor inflammatory response, we have both expressed a potent costimulator in oncogene-expressing beta cells and increased the abundance of reactive T cells. Coexpression of the costimulator B7.1 and the Tag oncoprotein leads to destruction of normal and premalignant islets and severe diabetes. Nevertheless, Tag+ tumors eventually develop, evidencing significantly reduced B7.1 expression and no infiltration. Another approach, whereby the abundance of reactive T cells was increased in double transgenic mice expressing Tag and a Tag-specific, CD4+-restricted T-cell receptor, was similarly unable to elicit tumor infiltration and destruction. Thus, neither costimulatory tumor cells nor hyperactivated antitumor lymphocytes were sufficient to produce an effective tumor immune response. In contrast, adoptive transfer of lymphocytes activated ex vivo did result in modest tumor infiltration with a limited induction of high endothelial venules on tumor vasculature, provided that T cells were transferred into irradiated recipients. However, adoptive transfer of ex vivo activated lymphocytes did not produce the dramatic inflammation seen in premalignant lesions. Thus, in addition to the parameters of activation and abundance of antitumor lymphocytes, the tumor microenvironment is evidently a critical parameter that can suppress lymphocyte extravasation and/or function inside tumors, likely in part via distinctive properties of the tumor vasculature.
Ganss
R
R
Department of Biochemistry and Biophysics, Hormone Research Institute, University of California-San Francisco 94143-0534, USA.
Hanahan
D
D
D007516:Adenoma, Islet Cell / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000209:etiology; D004730:Endothelium, Vascular / Q000502:physiology; D016219:Immunotherapy, Adoptive; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy*; D013539:Simian virus 40 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000952:Antigens, Polyomavirus Transforming; D007328:Insulin