Regulatory T cells and immune tolerance to tumors
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Regulatory T cells and immune tolerance to tumors Xuefang Cao
Published online: 10 September 2009 Ó Springer Science+Business Media, LLC 2009
Abstract Immune cells infiltrate tumors and make up a significant component of the multicellular cancer micro-environment, yet the immune system often fails to prevent tumor formation and progression. One explanation for this paradox is the presence of tolerance-promoting regulatory T cells (Tregs) that counteract antitumor immune cells. Tregs were known to be essential for maintaining self-tolerance. Recently, Tregs have been found to promote tolerance to tumors in mouse models. Moreover, Treg infiltration in human tumors and malignant ascites is associated with worse clinical outcomes for various types of cancers. As many reviews have discussed the development and function of Tregs, this review focuses on the cellular and molecular mechanisms by which Tregs influence antitumor immune responses, and also discusses how these mechanisms might be exploited to develop innovative immune-based approaches that can improve cancer therapy. Keywords Regulatory T cells (Tregs) Self-tolerance Tumor immunity Tumor micro-environment Immunotherapy
Introduction Clinical observations and animal models have established that the immune system responds to tumors even though they are derived from the host. Due to genetic and epigenetic changes associated with carcinogenesis, tumor cells can express antigens that elicit immune responses. Studies with RAG-/- mice (lacking T cells, B cells, and NKT cells) demonstrated that lymphocytes protect mice against tumor formation [1–3]. Both adaptive and innate immunity are important for preventing primary tumor formation and for rejecting transplanted tumors [1, 4, 5]. CD8? T cells, as a major effector compartment for antigen-specific antitumor immunity, can recognize and kill malignant cells that present antigen peptides with MHC I molecules [4, 6, 7]. Natural Killer (NK) cells can kill MHC X. Cao (&) Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA e-mail: [email protected]
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Immunol Res (2010) 46:79–93
I-deficient tumor cells in vivo and can prevent tumor formation and metastasis in mice [3, 8, 9]. Mice depleted of NK cells were more susceptible to chemically induced tumorigenesis [3]; mice genetically deficient for NK cells displayed severe defects in clearing transplanted MHC I-deficient tumor cell lines [10]. At the molecular level, interferons help to prevent tumor formation or influence the immunogenicity of tumors [1, 11], while the perforin/granzyme pathway and the Fas/FasL pathway account for contactmediated cytotoxicity delivered by NK and CD8? T cells [12, 13]. Despite the observations that activated, tumor-specific immune cells exist in cancer patients, the immune system frequently fails to prevent tumor formation and metastasis. Thus, tumors must be able to escape or suppress immunity in order to progress to advanced stages. Therefore, understanding the mechanisms
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