Concepts and ways to amplify the antitumor immune response.

In this chapter, a detailed description of how the innate and adaptive immune responses interact with malignant cells is presented. In addition, we discuss how developing tumors establish themselves, and how they benefit on one hand and organize their defense against the immune system on the other hand. New data from three tumor model systems in mice are discussed; in particular, the intricate interactions between the immune cells and the tumor cells are highlighted. With the present data and knowledge, we conclude that a first prerequisite for the combat against tumors is the activation of the innate immune system via external danger signals or damage signals and internal danger signals. The second prerequisite for efficient tumor cell eradication is combined therapeutic approaches of physical, chemical, pharmacological, and immunological origin. Finally, we propose new ways for further investigation of the relationship linking tumor cells and our defense system. It appears mandatory to understand how the malignant cells render the adaptive immune cells tolerant instead of turning them into aggressive effectors and memory cells. Perhaps, the most important thing, for immunologists and clinicians, to understand is that tumor cells must not be viewed just as antigens but much more.

The innate immune system recognizes and regulates major histocompatibility complex class I (MHCI) expression on MHCIlow tumor cells.

Tumor cells and the immune system play a lethal "pas de deux" during tumor development. However, it is not clear which role the innate immune system plays in these interactions. We studied the interaction of normal spleen cells (NSCs) with tumor cells expressing low levels of MHCI on the cell surface. This interaction induces increased MHCI expression on the MHCI(low) tumor cells by a cell-cell contact-dependent, IFN-gamma-mediated mechanism. The effector cells responsible for the increased IFN-gamma production were identified as CD4+ CD1d-independent NKT cells, NK1.1+ NK cells and CD4+ CD11c+ DCs. The possible three cell collaboration is not activated by MHCI(high) tumor cells or normal fibroblasts. Kinetic experiments showed that the increase in IFN-gamma production induced by MHCI(low) tumor cells happens in two consecutive waves, an early peak around 12 hours, followed by a second more important peak around day 2-3. Thus, we propose that CD4+ CD1d-independent NKT cells are activated by the MHCI(low) tumor cells, they release IFN-gamma stimulating DCs to produce IL-12, which in turn activates NK cells to produce large amounts of IFN-gamma. The recognition mechanism used by the CD4+ CD1d-independent non-classical NKT cells is unknown. Monoclonal antibody (mAb) blocking experiments using antibodies against either activating or inhibitory receptors or co-receptors on NKT/NK cells gave no conclusive results. Moreover, NSCs from either normal or MHCII(-/-) mice augmented MHCI expression on MHCI(low) tumors, excluding a significant role of CD4-MHCII interactions in the system. Hence the initial recognition mechanism in this system still awaits further experimentation.

The mouse immune response to human fibrinogen reveals an autoimmune component against mouse fibrinogen.

The present experiments were carried out to analyze whether immunization of mice with human fibrinogen would induce autoimmunity like other heterologous proteins such as collagen type II, thyroglobulin or myelin basic protein. Our results demonstrate that human fibrinogen induces very strong immune responses in all mouse strains analyzed. Autoimmune responses with short-term memory to mouse fibrinogen are induced in genetically susceptible mice. These autoimmune Th2-type responses induce splenomegaly, enhanced coagulation times, and production of rheumatoid factors. The short-lived autoimmune memory was not regulated by either suppressor T cells or exhaustion of immune cells; rather this potentially dangerous autoimmune response was regulated by unknown, antigen-specific feedback mechanisms (they do not influence immune responses to proteins like HSA and OA in the same mice). Such feedback mechanisms were not found in the immune responses to other heterologous proteins inducing significant cross-reactive autoimmunity such as collagen type II, thyroglobulin, or myelin basic protein.

Self-reactive T cell receptor-reactive CD8+ T cells inhibit T cell lymphoma growth in vivo.

Syngenic C57BL/6 mice (H-2(b)) vaccinated with mitomycin C-treated L12R4 T lymphoma cells develop protective immunity toward the MHC class II-negative tumor cells. In the present study, we characterize the nature, mode of function, and specificity of the effector cells in this immunity. These cells are TCR-specific CD8(+) T lymphocytes with effector function in vitro as well as in vivo upon transfer to naive mice. They produce high levels of IFN-gamma and TNF-alpha, but little or no IL-4. By means of TCRbeta-negative variant L12R4 cells, P3.3, and TCR-Vbeta2 cDNA-transfected and TCR-Vbeta2-expressing P3.3 lymphoma cells, we found that a significant part of the effector T cells are specific for the Vbeta12 region. The growth inhibition of L12R4 cells in vitro was inhibited by anti-H-2, anti-K(b), and anti-D(b) mAb. Furthermore, vaccination with Vbeta12 peptide p67-78, which binds to both K(b) and D(b) MHC class I molecules, induces partial protection against L12R4 T lymphoma cells. Thus, self-reactive TCR-Vbeta-specific, K(b)-, or D(b)-restricted CD8(+) T cells mediate inhibition of T cell lymphoma growth in vitro and in vivo.