Interactions between antigen presenting cells and CD4+ T cells in the generation of anti-tumor immunity.

摘要

Clinical and experimental evidence suggest that tumors are weak immunogens. A number of factors could contribute to this observation, including direct immunosuppression by the tumor, inadequate CD4+ T cell help, and deficient function of dendritic cells (DC), potent inducers of T cell immunity. Understanding the mechanisms by which the immune system responds (or does not respond) to tumors is paramount to designing effective immunotherapeutic strategies to combat malignancy. To determine whether immunosuppression is a general property of tumors, a panel of tumor cell transfectants was engineered that express cell surface, intracellular and secreted proteins as model tumor antigens. BALB/c derived tumors (line 1 and EMT6) could induce high titer antigen specific IgG antibodies to all types of antigens tested that were equivalent to antigen emulsified in adjuvants. In contrast, the C57BL/6 derived B16 melanoma failed to elicit antibody responses. This result was not due to strain differences, but rather to intrinsic properties of the different tumors studied.; The appearance of IgG antibodies suggested that CD4+ T cells were activated in response to line 1 tumors, however, the question remained whether the frequency of tumor specific CD4+ T cells was sufficient to generate anti-tumor CD8+ cytotoxic T lymphocytes (CTL). Utilizing line 1 tumors transfected with ovalbumin as a model tumor antigen and the adoptive transfer of OVA-specific CD4+ cells demonstrated that tumor specific CD4+ cells could be activated in response to tumors, however, the increased frequency of these cells had no effect on the generation of tumor specific CTL.; The failure of CD4+ cells to elicit CTL was due to antigen presentation by tumor activated B cells and limited mobilization of DC. The addition of IL-3 increased the DC population and induced anti-tumor CTL. In B cell deficient mice, IL-3 expressing tumors enhanced CTL generation and slowed tumor growth. Cytokine generated DC could protect BALB/c mice from lethal tumor challenge whereas immunization with B cells demonstrated only partial protection. Therefore, in this system, the balance of cell types responsible for antigen presentation determines effective anti-tumor immunity and shifting that balance to class I restricted presentation by DC increases tumor specific CTL.