Tumor cell recognition by T cells is first mediated by the interaction of T cell receptors on the surface of T cells with peptides bound to major histocompatibility complex (MHC) molecules on the surface of APCs, such as DCs (Fig. 33-1). This is termed "signal 1." Two other signals are needed for T-cell activation. Signal 2 is elicited via costimulation of T cells through binding, for example, of costimulatory molecules (B7-1, B7-2) on DCs to CD28 on T cells (see Fig. 33-1), and signal 3 comes from cytokines secreted by DCs (e. g., IL-12), which aid in sustaining the T cell-mediated antitumor response. Altogether, these signals promote activation, proliferation, and maturation of Cd8+ T cells, also referred to as CTLs. Signal 1 alone is thought to promote naive T-cell inactivation by anergy (lack of reaction), deletion, or development of a regulatory T-cell fate, thus leading to "tolerance."14 Signal 2 (costimulation) is required along with signal 1 for the induction of immunity. Signal 3 (cytokines) is also important because it affects the fate of T-cell differentiation—that is, into a Th1, Th2, or CTL effector T cell.14

There are two modes of antigen presentation that can lead to T-cell recognition of tumor antigens. In the first, direct antigen presentation (i. e., direct priming of T cells), the tumor cell serves as the APC to present peptide/MHC directly to T cells15 (see Fig. 33-1). The second mode of antigen presentation occurs when tumor antigens (from apoptotic or necrotic tumor cells), tumor-derived heat shock proteins, or tumor-derived exosomes are phagocytosed by APCs and presented in the context of their MHC class I or II to CTLs or Th. This process is referred to as cross-presentation (i. e., cross-priming ofT cells)15-17 (see Fig. 33-1).

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