Immune surveillance: a balance between protumor and antitumor immunity
Introduction
The concept that the immune system can be harnessed as a therapeutic agent to treat established tumors (immunotherapy) was first proposed in the early 1900s by Paul Ehrlich. He suggested that molecules that we now know as antibodies could deliver toxins directly to cancer cells. Ehrlich's ‘magic bullet’ strategy was expanded upon in the 1950s by Burnet and Thomas. They hypothesized that the immune system may also protect against nascent cancers by destroying malignant cells before they developed into detectable tumors, a concept that has become the immune surveillance hypothesis [1, 2]. Although enthusiasm for the validity of immunotherapy and immune surveillance waned in the 1970s, subsequent studies demonstrated that the immune system can protect against tumor onset and be manipulated to reject established tumors. Revival of the immune surveillance hypothesis led to a re-working of the initial concept, to include the concept of ‘immunoediting.’ During immunoediting, the immune system destroys many precancerous and malignant cells; however, some cells escape the immune response and give rise to progressively growing tumors. Immunoediting is thought to continue throughout the life of the tumor so that the phenotype of an established tumor has been directed by the host's immune response. It has also become apparent that both innate and adaptive immunity have a ‘dark’ side and can promote tumor progression as well as mediate tumor destruction. Not surprisingly, chronic inflammation, which has long been associated with increased tumor risk, is involved in polarizing immunity toward those effectors that facilitate tumor growth. As a result, the immune system has the potential to either promote or delay tumor onset and progression, and the effectiveness of immune surveillance and the efficacy of immunotherapy depend on the balance between these diametric opposites (Figure 1). After a brief over-view of the observations supporting the concept of immune surveillance, this article will review the cells that mediate protumor and antitumor immunity including a discussion of how inflammation polarizes innate and adaptive immunity toward either a protumor or antitumor phenotype.
Section snippets
Immune surveillance and immunoediting
Rejuvenation of the concept that the immune system protects against nascent malignant cells occurred with the demonstration that mice deficient for various components of the adaptive or innate immune systems were more likely to develop some types of tumors, specifically sarcomas as opposed to carcinomas, as compared to immune competent mice, when exposed to carcinogens or transplanted with syngeneic tumor cells. Immune deficiencies included the absence of B cells and αβ or γδ T cells because of
CD4+ and CD8+ T lymphocytes
CD4+ and CD8+ T cells are the principal helper and effector cells, respectively, of adaptive cellular immunity, and many immunotherapy strategies are aimed at activating these cells to promote tumor cell destruction and long-term immune memory against recurrence of primary disease or outgrowth of metastases. Type 1 CD4+ T cells (Th1) facilitate tissue destruction and tumor rejection by providing help to cytotoxic CD8+ T cells, while Type 2 CD4+ T cells T(Th2) facilitate antibody production by B
B lymphocytes
Tumor-reactive monoclonal antibodies can have significant antitumor efficacy when passively administered to cancer patients. By contrast, most cancer vaccines or other therapies that are aimed at inducing tumor-reactive antibodies are largely ineffective in promoting tumor rejection, though there are exceptions [19]. More recent experiments indicate that activated B cells and their soluble products, presumably antibodies, can also facilitate carcinogenesis. Using a transgenic mouse model in
Macrophages
Macrophages are part of the innate immune system and play important roles in all aspects of immunity. They are an exceptionally heterogeneous population of cells. Similar to CD4+ T cells, macrophages can contribute to tumor destruction or facilitate tumor growth and metastasis, depending on their phenotype (Figure 3).
Macrophages that are ‘classically activated’ by IFNγ and bacterial lipopolysaccharides destroy tumor cells through their production of nitric oxide and Type 1 cytokines and
Natural killer (NK) cells
NK cells are components of the innate immune system that interact with adaptive immunity through their production of cytokines that modulate dendritic cell (DC) and cytotoxic T cell maturation. They are well recognized for their ability to directly lyse MHC class I-deficient tumor cells through the engagement of their activating receptors and lack of engagement of their inhibitory receptors. However, a subset of NK cells are also cytotoxic for activated CD8+ T cells [32] and DC [33], and
NKT cells
NKT cells, which express both NK and TCR, bridge the innate and adaptive immune systems. They are usually CD4+ and respond to lipid and glycolipid antigens as presented by nonclassical MHC class I CD1d molecules. Until recently there was confusion as to whether NKT cells promote tumor rejection or enhance immune surveillance. NKT cells prevent the spread of B16 melanoma metastases and promote immune surveillance in mice treated with the carcinogen 3-methyl-cholanthrene. However, CD1d knockout
Myeloid-derived suppressor cells (MDSCs)
MDSC are a morphologically and functionally heterogenous population of cells of myeloid origin that are elevated in almost all patients and experimental mice with cancer [37]. They suppress both innate and adaptive antitumor immunity by inhibiting CD8+ and CD4+ T cells, NK and NKT cells, and by blocking DC maturation [38, 39•, 40, 41]. MDSC suppress T cells through their production of arginase and/or reactive oxygen species (ROS); however, there is variability in which mediator(s) is used
Conclusions
The immune system has the capacity either to block tumor development and deter established tumors, or to promote carcinogenesis, tumor progression, and metastasis. Which of these conditions prevails depends on the balance between the protumor and antitumor mediators of both innate and adaptive immunity. Presumably, there are unifying mechanisms that orchestrate immunity towards tumor promotion versus tumor destruction. Since many of the tumor-promoting elements of the immune system are induced
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The author's laboratory is supported by National Institute of Health grants R01CA118550 and R01CA84232, and Susan G. Komen Foundation for the Cure BCTR0503885.
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