Abstract
Although the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.
Highlights
The onset, expansion, persistence, and spreading of tumors are under the control of a complex series of events that encompass both intrinsic modifications of cancer cells, such as genetic mutations in proto-oncogenes and in tumor suppressor genes, and alteration of the apoptotic process, which cumulatively impact on the homeostasis of the cell cycle, as well as extrinsic mechanisms related to the capacity of the host to counteract tumor growth [1]
The genetic modifications affecting tumor cells may lead to the generation of structurally altered or abundantly synthesized proteins that may be seen by the immune system as new antigens or “non-self ” products against which the system has not learned to be tolerant during ontogenesis [3]
In some circumstances tumor cells may express MHC class II molecules, these cells are believed to act at most as “peptide antigen presenters” to antigen-specific primed T helper (TH) cells but not as “antigen processors and presenters” for naïve TH cell priming. This is only partially true, since we have demonstrated that, at least in vitro, human or murine engineered-tumor cells, stably expressing MHC class II molecules, can process protein antigens and present relevant peptides to MHC-II-restricted antigen-specific T cell clones [21, 22]. These results have shown that the intracellular machinery responsible for digesting and exposing MHC-II–peptide complexes on the cell surface for TH cell recognition may work properly in cells which are not classical antigen presenting cells (APCs), and notably in MHC-II-positive tumor cells
Summary
The onset, expansion, persistence, and spreading of tumors are under the control of a complex series of events that encompass both intrinsic modifications of cancer cells, such as genetic mutations in proto-oncogenes and in tumor suppressor genes, and alteration of the apoptotic process, which cumulatively impact on the homeostasis of the cell cycle, as well as extrinsic mechanisms related to the capacity of the host to counteract tumor growth [1]. The fact that most tumor cells do not express MHC class II molecules prevents even the possibility that these cells may act as potential APCs for their TAAs and by consequence that they may trigger tumor-specific TH cells.
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