Cancer cells frequently stimulate Signal 1 alone, and inefficiently stimulate Signal 2. Accordingly, cancer cells may preferentially induce tolerance. Hence, tumor antigens must be presented through antigen-presenting cells to initiate and sustain anti-tumor immune responses. This is achieved by a process called APCs such as DCs can efficiently prime T cells, where they display MHC antigen complexes (Signal 1) together with co-stimulatory molecules (Signal 2), which activate naïve T cells in a process called cross-priming. This process can also cause T cell unresponsiveness or cross-tolerance (Chapters 7 and 11 in Immunology IV).
Since individual B and T lymphocytes are antigenically committed to a specific unique antigen, their clonal expansion upon recognition of foreign antigens is required to obtain sufficient antigen-specific B and/or T lymphocytes to achieve an appropriate immune response. Although the kinetics of primary adaptive immune responses are slower than innate immune responses, the differentiation of lymphocyte subsets into long-lived and short-lived memory cells during the primary immune response results in larger responses upon subsequent exposure to the same antigen (Figure 2 and Chapter 6in Immunology IV).
T Cytotoxic and NK Cell Killing of a Cancer Cell
Two of the major cytotoxic killing mechanisms of tumors are carried out by either CD8+ CTL cells or NK cells (Chapters 1 and 3in Immunology IV). Shown in Figure 3 is a schematic representation of the mechanism of destruction of a cancer cell by a CTL cell. After generation of mature CTL cells resulting from the APC-antigen/T cell interaction as described previously, the presence of the tumor peptide-loaded MHC-I molecule on the surface of the cancer cell is required for effective tumor cell killing. In this scenario, where the cancer cell retains the MHC-I molecule, the CTL cell is activated to kill the cancer cell by apoptosis.
During the course of malignant transformation of a normal cell to a malignant cell, the cancer cell may lose the MHC-I molecule on its cell membrane as part of its evasion strategy to elude its destruction by the CTL. In this scenario, the NK cells are now called into play. Shown in Figure 4 is a schematic representation of the mechanisms of killing of a tumor cell by the NK cell. Normally, NK cells display two types of receptors: (1) a killer-activating receptor (KAR) with specificity for a number of cell surface ligand molecules; and (2) a killer-inhibitingreceptor (KIR) with specificity for a MHC-I ligand. The interaction of a NK cell with a normal cell consists of the binding of both of these receptors with their respective ligand molecules, which are found on the cell membrane of a normal cell; the binding of the KAR with an KAR activation ligand (L) on a cell leads to an activation signal that enhances the killing activity of the cell, and conversely the binding of the KIR with an MHC-I molecule ligand results in an inhibitory signal restraining the killing activity of the cell. Since the inhibitory activity of the KIR-MHC-I interaction is greater than the killing activity of the KAR-L interaction, no reaction is seen when a NK cell encounters a normal cell. In the event of the loss of expression of a MHC-I molecule by the cancer cell, since the NK interaction with the cancer cell now can only occur through the KAR ligand, the cancer cell will be killed by the unopposed KAR activation pathway. The apoptotic killing mechanism involves the assembly of a membrane-associated perforin cylindrical structure into which the granzymes deliver their death-dealing blow (Chapters 1 and 3 in Immunology IV).
An alternative mechanism of destruction of the tumor cell by an NK cell can occur by an ADCC mechanism where the Fab portion of an IgG antibody produced by B cells binds to the surface TSA and bridges to an Fc receptor on the NK cell by attachment through its Fc portion of the antibody molecule (Chapters 1 and 3in Immunology IV). Shown in Figure 5 is comparison of these two mechanisms of killing of a cancer cell by a NK cell.