Tumors express antigens that should induce immune-mediated rejection, but spontaneous rejection of established tumors is rare. Recent work demonstrates that one reason for the lack of tumor rejection is that tumors actively defeat host immunity. This concept forces us to rethink current approaches to harnessing potent, specific host immunity to battle cancer, most of which are based on the paradigm that inducing more antitumor immune cells alone is therapeutic. However, as I discuss in this Personal Perspective, a newer paradigm predicts that reducing tumor-driven immune suppression will be clinically beneficial. CD4+CD25+ Tregs are one mechanism of tumor-driven immune evasion that provide prototypical targets for testing novel anticancer treatment strategies within the newer paradigm.
Tyler J. Curiel
Because of the large preexisting antigenic load and immunosuppressive environment within a tumor, inducing therapeutically useful antitumor immunity in cancer patients requires the development of powerful vaccination protocols. An approach gaining increasing popularity in the tumor vaccine field is to immunize cancer patients with their own DCs loaded ex vivo with tumor antigens. The underlying premise of this approach is that the efficiency and control over the vaccination process provided by ex vivo manipulation of the DCs generates an optimally potent APC and a superior method for stimulating antitumor immunity in vivo compared with the more conventional direct vaccination methods, offsetting the added cost and complexity associated with this form of customized cell therapy.
Eli Gilboa
The ability of the immune system to identify and destroy nascent tumors, and to thereby function as a primary defense against cancer, has been debated for many decades. Recent findings by a number of investigators in both mouse models of cancer and humans with cancer now offer compelling evidence that particular immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor suppressor mechanisms. This work provides the basis for further study of natural immunity to cancer and for rational use of this information in the design of immunotherapies in combination with other conventional cancer treatments.
Jeremy B. Swann, Mark J. Smyth
In vertebrates, the TLRs are a family of specialized immune receptors that induce protective immune responses when they detect highly conserved pathogen-expressed molecules. Synthetic agonists for several TLRs, including TLR3, TLR4, TLR7, TLR8, and TLR9, have been or are being developed for the treatment of cancer. TLR9 detects the unmethylated CpG dinucleotides prevalent in bacterial and viral DNA but not in vertebrate genomes. As discussed in this Review, short synthetic oligodeoxynucleotides containing these immune stimulatory CpG motifs activate TLR9 in vitro and in vivo, inducing innate and adaptive immunity, and are currently being tested in multiple phase II and phase III human clinical trials as adjuvants to cancer vaccines and in combination with conventional chemotherapy and other therapies.
Arthur M. Krieg
Tumors require a constant influx of myelomonocytic cells to support the angiogenesis and stroma remodeling needed for their growth. This is mediated by tumor-derived factors, which cause sustained myelopoiesis and the accumulation and functional differentiation of myelomonocytic cells, most of which are macrophages, at the tumor site. An important side effect of the accumulation and functional differentiation of these cells is that they can induce lymphocyte dysfunction. A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response.
Antonio Sica, Vincenzo Bronte
The transfusion of T cells, also called adoptive T cell therapy, is an effective treatment for viral infections and has induced regression of cancer in early-stage clinical trials. However, recent advances in cellular immunology and tumor biology are guiding new approaches to adoptive T cell therapy. For example, use of engineered T cells is being tested as a strategy to improve the functions of effector and memory T cells, and manipulation of the host to overcome immunotoxic effects in the tumor microenvironment has led to promising results in early-stage clinical trials. Challenges that face the field and must be addressed before adoptive T cell therapy can be translated into routine clinical practice are discussed.
Carl H. June
It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumor growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumor progression. However, inflammatory cells also produce cytokines that can limit tumor growth. Here we provide an overview of the current understanding of the role of inflammation-induced cytokines in tumor initiation, promotion, and progression.
Wan-Wan Lin, Michael Karin
Models of liver fibrosis, which include cell culture models, explanted and biopsied human material, and experimental animal models, have demonstrated that liver fibrosis is a highly dynamic example of solid organ wound healing. Recent work in human and animal models has shown that liver fibrosis is potentially reversible and, in specific circumstances, demonstrates resolution with a restoration of near normal architecture. This Review highlights the manner in which studies of models of liver fibrosis have contributed to the paradigm of dynamic wound healing in this solid organ.
John P. Iredale
The CXC chemokine family is a pleiotropic family of cytokines that are involved in promoting the trafficking of various leukocytes, in regulating angiogenesis and vascular remodeling, and in promoting the mobilization and trafficking of mesenchymal progenitor cells such as fibrocytes. These functions of CXC chemokines are important in the pathogenesis of pulmonary fibrosis and other fibroproliferative disorders. In this Review, we discuss the biology of CXC chemokine family members, specifically as it relates to their role in regulating vascular remodeling and trafficking of circulating mesenchymal progenitor cells (also known as fibrocytes) in pulmonary fibrosis.
Robert M. Strieter, Brigitte N. Gomperts, Michael P. Keane
The unrelenting and destructive progression of most fibrotic responses in the pulmonary, cardiovascular, integumentary, and alimentary systems remains a major medical challenge for which therapies are desperately needed. The pathophysiology of fibrosis remains an enigma, but considerable research and debate surrounds the question of whether chronic inflammation is the key driver of unrestrained wound healing (i.e., the fibrotic response) in these and other organ systems. This Review describes how infectious pathogens, chronic inflammation, and unrestrained fibroproliferation are likely to be part of a dynamic, unrelenting process propelling human fibrotic diseases.
Alessia Meneghin, Cory M. Hogaboam
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