Basic Models of Tumor-Immune System Interactions Identification, Analysis and Predictions

We present a mathematical model of the cytotoxic T lymphocyte response to the growth of an immunogenic tumor. The model exhibits a number of phenomena that are seen in vivo, including immunostimulation of tumor growth, "sneaking through" of the tumor, and formation of a tumor "dormant state". The model is used to describe the kinetics of growth and regression of the B-lymphoma BCL1 in the spleen of mice. By comparing the model with experimental data, numerical estimates of parameters describing processes that cannot be measured in vivo are derived. Local and global bifurcations are calculated for realistic values of the parameters. For a large set of parameters we predict that the course of tumor growth and its clinical manifestation have a recurrent profile with a 3- to 4-month cycle, similar to patterns seen in certain leukemias.

Natural killer cells lyse tumor and virally infected cells in a specific manner that has not been molecularly characterized. Target cell expression of major histocompatibility complex (MHC) class I molecules is correlated with target cell resistance to natural killing. A mechanism to explain this observation is that NK cells may display two types of recognition and activation molecules that have opposing functions when bound to target cell ligands. One type of surface receptor such as the NKR-P1 molecule may activate NK activity whereas the other, represented by the mouse Ly-49 molecule, may engage target cell MHC molecules and inhibit cytotoxicity by transducing "negative" signals. NKR-P1 and Ly-49 are structurally related, and they are encoded by genetically linked loci in a chromosomal region, termed the NK gene complex (NKC), on distal mouse chromosome 6. Target cell susceptibility to natural killing may be dependent upon specific ligand-receptor interaction with these activating or inhibitory NKC-encoded molecules.

The characteristics of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell recognition of and binding to target cells (conjugate formation), and the precise mechanism(s) by which the target cells are triggered to undergo apoptotic cell lysis are now being deciphered at the cellular and molecular levels. Involvement of a multitude of cell surface molecules, in addition to T cell receptor (TCR)-major histocompatibility (MHC)-peptide complexes, in the binding and signalling for lymphocyte-mediated lysis has been demonstrated. Two proposed mechanisms of lymphotoxicity currently appear to be valid: (i) a membranolytic one initiated by the formation of pores in target cell membranes by secreted molecules of lymphocyte origin, such as perforin and granzymes, and (ii) a nonsecretory one initiated by receptor-mediated triggering of apoptosis-inducing target cell surface molecules, but not involving the secretion of pore-forming agents and granzymes. Perforin and granzymes are probably involved in lymphocyte activation and are likely mediators of the membranolytic pathway of lymphotoxicity. Existence of the nonsecretory and receptor-triggered lytic mechanism was indicated by (i) the prelytic fragmentation of the target cell's DNA, which precedes release of intracellular (51Cr-labeled) components, (ii) the demonstration of cytolytic effector cells that are either devoid of or express background levels of lytic granules and perforin, and (iii) the observation that some CTL lyse target cells under conditions at which perforin and granzymes are neither secreted nor lytic, e.g. [Ca2+]o < 1 micromolar. These two mechanisms are not mutually exclusive and are probably used by different types of effector cells or by the same effector cells at different stages of differentiation. In fact, recent perforin gene knock-out experiments support the existence of both.