Mutations, genomic instability, and epigenetic modifications provide potential tumor antigens for therapeutic targeting. These same mechanisms, however, also facilitate tumor escape from immune recognition and elimination, and thus present formidable obstacles to effective vaccination strategies.
First proposed by Burnet and Thomas, the cancer immunosurveillance hypothesis states that tumor cells can be recognized and eliminated by the immune system before the manifestation of clinical symptoms (19
). Accordingly, it is reasonable to speculate that cancer vaccines might be useful throughout the spectrum of cancer development. Recent sophisticated studies in murine models provided much-needed support for this hypothesis, revealing the critical roles of interferon gamma (IFN-γ) and lymphoid populations in cancer immunosurveillance. However, IFN-γ and lymphoid cells were also shown to alter the tumor itself by decreasing immunogenicity and facilitating growth in immunocompetent animals (21
). In an effort to incorporate the tumor-modulating effects of the immune system into the original immunosurveillance hypothesis, Schreiber and colleagues introduced the concept of cancer immunoediting, which encompasses the processes of elimination, equilibrium, and escape (20
). During the elimination phase, which corresponds to immunosurveillance, innate lymphoid cells recognize and eliminate accumulated transformed cells. This protective response exerts a selective pressure on genetically unstable transformed cells, allowing them to evolve and persist in a dynamic equilibrium with the immune response (20
). The equilibrium phase may last for many years until transformed cells acquire the ability to evade and escape the immune response and manifest as clinically evident disease (20
How do transformed cells reach the equilibrium and escape phases? A growing body of evidence suggests that genomic instability provides tumors with the ability to produce immunomodulatory factors that can inhibit immunosurveillance. One such factor, transforming growth factor-beta (TGF-β), is produced by many solid tumors and has profound immunosuppressive activity, including the inhibition of DC maturation and T cell proliferation and activation. TGF-β also promotes the accumulation of T regulatory cells (Tregs) that serve to further suppress cellular immunity. Tregs play an important role in suppressing the immune response to endogenous antigens, and the accumulation of Tregs in the tumor microenvironment is associated with poor clinical outcomes (22
). Depletion of Tregs in conjunction with cytokine therapy has been shown to increase anti-tumor immunity by enhancing the expansion of tumor-infiltrating CTLs (23
). Other soluble mediators, such as interleukin 10 (IL-10), may also suppress effective anti-tumor cellular immunity. IL-10 can activate signal transducer and activator of transcription 3 (STAT3), resulting in the accumulation of immature DCs and Tregs in the tumor microenvironment (24
). STAT3 is constitutively expressed by many solid tumors and results in the production of IL-10 and TGF-β, thus further inhibiting anti-tumor immunity (24
). Although STAT3 inhibition is associated with tumor regression and enhanced anti-tumor immune responses (25
), the overall effect of IL-10 on anti-tumor immunity remains to be determined since several groups have reported that IL-10 can be beneficial to the anti-tumor immune response (28
Tumor escape also may be facilitated by activation of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). In the setting of chronic inflammation, a subset of DCs upregulates IDO expression. This action promotes the differentiation of naïve cluster of differentiation 4 (CD4)+ T cells into Tregs and enhances the immunosuppressive activity of mature Tregs (29
). Therefore, targeting tumor-derived immunosuppression may synergize with vaccination strategies to unleash and amplify the host’s anti-tumor immune response.