Pharmacology of Tumor Cell – Immune Cell Interactions
The discussion on molecules that can augment the interactions between immune cells and tumors is based on three different possible mechanisms: molecules that can interfere with
(1) specific, clonal interactions;
(2) specific, non-clonal interactions; or
(3) non-specific, global reactions.
The big disadvantage of the latter two possibilities is that such treatments may also attain functions other than the specific immune cell-tumor interaction. Interactions between KARs, co-receptors, or immunoglobulins (Ig) and tumorigenic cells are mediated by receptors reacting with their membrane-bound ligands on the cells. The interaction between the TCRs and tumorous cells is more complex for several reasons:
First, TCR recognizes composite ligands (pMHC) with such a low avidity that a simultaneous interaction of co-receptors (e.g., CD4, CD8, CD28, and CD154) and/or adhesion receptors (e.g., CD2, LFA-1) is necessary to trigger T cell activation. These two co-signals augment the messages sent through the different intracellular signal transmission pathways. Consequently, not only the TCR- pMHC interaction (the clonal signal
1) is a target for potentiating drugs but also the interactions between the co-receptors or adhesion receptors (the non-clonal signal
2) on T cells and their ligands on APC are possible, non-specific drug targets.
Second, there are two levels of interactions between TCR and tumor antigens:
(1) initial activation recognition and
(2) effector cell recognition. In responses against tumor cells, these two processes are separated by the fact that CD4+ Th cells need MHCII to be triggered and the CD8+ effector CTL are MHCI restricted. As tumor cells are frequently MHCII, the Th cell activation process has to take place via a cross-presentation procedure, where APC takes up tumor cell antigen as immature DC in the local tumor, process it, and present it on the outer cell surface of mature DC in association with MHCII molecules in the draining lymph nodes. Activated CD4+ Th1 cells produce IL-2, which appears necessary and sufficient for CTL differentiation. Furthermore, CD8+ CTL activation is also dependent on the presence of mature DCs to initiate their differentiation program. Third, once the CD8+ effector cells are activated and have matured, they can interact with cell ligands directly, provided that the tumor cells do present tumor cell-specific peptides associated with MHCI molecules on their cell surface.
(1) a possible drawback of induction of antitumor immune responses is the potential risk of concomitant autoimmune reactions, and
(2) tumor does not contain “just” antigens, but cells that are self-sufficient in growth signals are insensitive to growth-inhibitory signals, evade programmed cell death (apoptosis), have limitless replicative potential, have sustained angiogenesis, have tissue invasive and metastatic properties, and have apparent resistance to the immune system once organized as an established tumor.
By the above discussion we can understand that tumor cells are quite different from simple antigens and further research is needed in this area to find immune response against tumor cells.
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