Communication between the immune system and tumor cells takes place via both cell-cell contact-dependent receptor-ligand interactions and released cytokines/chemokines. T lymphocytes of the adaptive immune system learn in the thymus to distinguish various self or altered self-structures from non-self-structures presented as peptides bound to major histocompatibility complex (MHC) class I or class II antigens (pMHC). pMHC molecules represent the antigenic universe to ab-T lymphocytes, both the self and the non-self-repertoire.
Gd-T lymphocytes recognize small phosphorylated molecules or non-classical MHCI antigens in a non-MHC restricted manner, and B lymphocytes recognize tertiary or quaternary structures of antigens using immunoglobulins (Ig). A third type of recognition is used by cells of the innate immune system: natural killer (NK) and natural killer T (NKT) cells recognize lack of expression of self (missing self), i.e., absence or low cell-surface levels of MHCI and/or MHCII molecules Furthermore, antigen-presenting cells (APC) such as dendritic cells (DC), macrophages, and granulocytes can recognize non-self-structures via toll-like receptors (TLR) or C-type lectin receptors (CLRs).
Activation of T cells, NKT, or NK cells happens via the interaction of activating receptors (KAR) associated with signaling molecules expressing immuno-tyrosineactivation- motif (ITAM) signal-motifs in their cytoplasmic region. T lymphocytes and NKT cells express T-cell receptor (TCR)/CD3 complexes, and T, NKT, or NK cells express KARs such as NKG2D associated with DAP10 signal-transduction molecules and Ly49D associated with DAP12 molecules. It appears that the high number (~10) of ITAMs associated with TCR molecules is necessary to avoid autoimmunity. Inhibition of cell activation by inhibitory receptors (KIRs) such as NKG2A/ CD94 is related to the expression by KIRs of ITIM inhibitory motifs in their cytoplasmic tails
Helper T (Th) cells trigger differentiation of precursor cells into CD8+ cytotoxic T lymphocytes (CTL) or antibody-producing B cells. The so-called Th1 cells induce preferentially the production of IL-2 and IFNg and the differentiation of CTL, whereas Th2 cells induce mostly the production of IL-4, IL-5, and IL-13 and the differentiation of B cells into antibody-producing plasma cells. When administered to elicit specific immune responses and memory but not tolerance, the antigens have to be presented in the form of cells, particles, or aggregates, or emulsified in adjuvants such as Freund’s adjuvants or aluminum salt precipitates. A unifying concept of these phenomena was proposed by late Charlie Janeway.
The innate immune system, NKT cells, NK cells, DC, macrophages, and granulocytes are activated by pathogenassociated molecular patterns (PAMPs) by means of TLR or CLRs. The DC differentiates from immature, phagocytosing cells to mature, non-phagocytosing cells with increased levels of co-stimulatory molecules such as MHCII, CD40, CD80, and CD86 and enhanced antigen-presenting activity. Cells from the innate immune system release inflammatory cytokines that induce the priming of CD4+ Th subpopulations (Th1, Th2, and Th17). Immediately after stimulation, NKT cells release preformed IFNg and IL-4 which direct Th1 and Th2 cell differentiation, respectively. IFNg triggers DC to produce IL-12, which induces preferential Th1-priming and NK cell production of IFNg and cytotoxicity. A subset of DCs, CD8+CD205+ dendritic cells, produces endogenous TGFb and is specialized to induce Foxp3+ Treg cells, whereas another subset, CD8 CD205 and DCIR-2+ (DC inhibitory receptor-2), participates in Th2 responses.
Although stimulation of the innate immune system may greatly help the initiation of adaptive cellular and humoral immune responses, over-activation of the innate immune system represents a risk due to a possible “fatal cytokine storm” However, the cytokine storm is prevented by CD4+ Th or CD8+ CTL, which down-regulate the activity of the innate immune cells by a cell-cell contact, MHC-dependent mechanism. It seems clear that memory T cells are derived from effector T cells by avoiding antigen-induced cell death. In contrast, the subdivision of CD4+ T cells into Th1, Th2, Th9, Th17, and Treg cells is more malleable and demonstrates more functional plasticity than previously thought.
Inexperienced, naive T cells appear to receive different types of “secondary education” when they encounter antigen at various regional sites including tumor micro environments. Besides possessing different effector functions, DC and T cells should be able to migrate to and within tissues. Adhesion via L-selectin induces rolling, activation, and transmigration via chemokine receptors such as CCR7. The interaction between CCR7 and its ligands, CCL19 and CCL21, may balance immunity and tolerance T lymphocytes do not react with self-structures that are expressed in normal physiological conditions, i.e., the organism is tolerant to self-structures.
However, thymus negative selection (central tolerance) is not infallible, and self-reactive Concepts and Ways to Amplify the Anti tumor Immune Response 99 T cells with low-avidity TCR do emigrate from the thymus. Such self-reactive T cells are regulated by CD4+CD25+ T regulatory (Treg) cells (peripheral tolerance). Thus, since many anti tumor immune responses are “autoimmune” reactions, these are often weak in both quantity and quality. It is important to distinguish between the following three levels of low responsiveness to malignant cells:
(1) tumor-specific T cells with high-avidity TCR have been eliminated in the thymus;
(2) tumor cells or their products may induce tolerance (in the sense of unresponsiveness), i.e., tumor-specific T cells are present but are rendered anergic;
(3) immune effectors recognize tumor cells but are prohibited from performing their natural function due to tumor-associated inhibitory molecules and/or cells.
The latter two phenomena are linked to the fact that resting DC or macrophages in the tumor induces and maintains peripheral tolerance and functional anergy in CD8+ T cells, NKT cells, and NK cells through PD-1 and CTLA-4-related mechanisms.
