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Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance

From the Department of Hematology and Oncology, University Medical Center Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany; and the Transplantation Biology Research Center, Bone Marrow Transplantation Section, Transplantation Biology Research Center Massachusetts General Hospital/Harvard Medical School, Boston, MA.

Address reprint requests to Megan Sykes, MD, Transplantation Biology Research Center, Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, MGH-E Bldg149-5102, Harvard Medical School, Boston, MA 02129; e-mail: Megan.Sykes{at}tbrc.mgh.harvard.edu

The development of malignant disease might be seen as a failure of immune surveillance. However, not all tumors are naturally immunogenic, and even among those that are immunogenic, the uncontrolled rapid growth of a tumor may sometimes out-run a robust immune response. Nevertheless, recent evidence suggests that mechanisms of tolerance that normally exist to prevent autoimmune disease may also preclude the development of an adequate antitumor response and that tumors themselves have the ability to thwart the development of effective immune responses against their antigens. A major challenge has been to develop approaches to breaking this tolerance in tumor-bearing hosts, and recent advances in our understanding of antigen presentation and tolerance have led to some promising strategies. An alternative approach is to use T cells from nontumor-bearing, allogeneic hosts in the form of lymphocyte infusions, with or without hematopoietic cell transplantation. Immunotherapy may occur in this setting via the response of nontolerant, tumor antigen-specific T cells from nontumor-bearing hosts or via the powerful destructive effect of an alloresponse directed against antigens shared by malignant cells in the recipient. Approaches to exploiting this beneficial effect without the deleterious consequence of graft-versus-host disease in allogeneic hematopoietic cell recipients are discussed.

Supported in part by National Institutes of Health/National Cancer Institute grants 1 R01 CA 79989-03 and 1 R01 CA 79986-03.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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