Chapter Two - Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines
Introduction
Metastatic disease, the main cause of cancer-related deaths, is driven by the ability of malignant tumors to disseminate and to colonize sites that are distant from the location of the primary mass (Hanahan & Weinberg, 2000). Frequently, tumor dissemination is also associated with refractoriness to a range of conventional anticancer therapies, including chemotherapy and radiation (Braun et al., 2000), and several molecular-targeted therapies (Thomson et al., 2005, Thomson et al., 2008). In light of the recent advances in the field of cancer immunotherapy, an attractive therapeutic alternative to address the problem of metastatic disease is the generation of a sustained immune response directed against essential molecular drivers of tumor progression. This chapter focuses on the current status of development of immune-mediated anticancer interventions aimed at preventing and/or treating metastatic disease. Among the topics discussed here are (a) the role of the epithelial–mesenchymal transition (EMT) in tumor dissemination and metastasis, (b) the association of EMT with tumor stemness and resistance to multiple anticancer therapies, (c) how therapeutic cancer vaccines can be used to target regulators of EMT, and (d) the potential for mitigation of metastatic disease by the use of combinatorial therapies of cancer vaccines and other agents that alleviate tumor EMT. While this chapter does not discuss in detail the numerous factors involved in the design and development of therapeutic cancer vaccines, comprehensive reviews on this topic can be found in the literature (Palena and Schlom, 2010, Schlom, 2012, Schlom et al., 2014).
Section snippets
EMT and Tumor Invasiveness
In order to metastasize, cancer cells undergo a series of events known collectively as the metastatic cascade, a process that involves their detachment from the primary tumor mass and invasion into the surrounding tissues, entrance into the circulation, homing in on distant organs, and survival and proliferation at secondary sites (Nguyen et al., 2009, Nguyen and Massague, 2007). Multiple studies have now demonstrated that carcinoma cells undergo profound phenotypic changes during progression
Targeting of EMT
Due to its critical role in cancer progression, targeting of EMT as a means of preventing metastasis, and possibly, of eliminating cancer cells that would otherwise resist most currently available therapies, is being considered as an attractive therapeutic alternative to the problem of metastatic disease (Palena et al., 2011). Some of the possible approaches that are being explored to inhibit the EMT involve the use of small-molecule agents that block the signaling pathways initiated by
Overcoming Potential Tumor Immune Resistance
While the associations of tumor EMT with tumor escape from conventional antineoplastic interventions or certain small-molecule targeted therapies, such as EGFR inhibitors, have been extensively documented, few reports have investigated whether tumor plasticity mediated by EMT could also mediate resistance to immune-mediated attack, potentially contributing to tumor escape from host immune surveillance and failure of immune-mediated rejection.
Some of the most studied mechanisms of immune evasion
Concluding Remarks
Progress in elucidating the molecular mechanisms that govern the process of metastasis, including a full understanding of the role of tumor EMT and its association with tumor stemness and resistance to therapies, will help in designing therapies better fitted at preventing and/or treating metastatic disease. Cancer vaccines able to specifically target metastatic tumor cells constitute a very attractive methodology. Unlike other modalities, vaccines may be able to generate a long-lasting
Acknowledgments
The authors thank Debra Weingarten for editorial assistance in preparation of this chapter.
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