Characterization of the molecular and cellular events associated with interleukin-12-induced suppression of human lung tumor/TIL xenografts.

摘要

One of the fundamental principles in tumor immunology is that human leukocytes influence tumor progression in cancer patients. A logical extension of this principle is the development of cancer immunotherapy which attempts to promote or enhance the anti-tumor activity of the immune system. While immunotherapy has been successful in animal models of cancer, the treatment of human malignancy has proven to be more difficult. Moreover, pre-clinical studies on human leukocyte/tumor cell interactions and immunotherapy have been limited in large part to in vitro experiments conducted with isolated cells. Therefore, the ability of human leukocytes to influence tumor progression in vivo and within the tumor micro environment (i.e. in situ) remains open to question.; The research presented in this thesis has focused on studying the functional capacity of human tumor-infiltrating leukocytes (TIL), in situ, by engrafting nondisrupted pieces of human lung tumor tissue into severe combined immuno-deficient (SCID) mice. This work establishes that local and sustained delivery of the proinflammatory cytokine, interleukin-12 (IL-12), to the microenvironment of human lung tumor xenografts induces a human TIL-dependent suppression of tumor growth in vivo.; IL-12 treatment stimulates the production of human IFN-γ, which is detected in the sera of tumor-bearing mice. In the IL-12-treated animals, serum levels of human IFN-γ correlate directly with the degree of tumor suppression observed. Neutralization of human IFN-γ in vivo results in the loss of IL-12-induced tumor suppression, indicating that IFN-γ is essential in mediating the anti-tumor activity of human TIL.; A detailed analysis of gene expression patterns within the microenvironment of lung tumor xenografts reveals that IL-12 treatment enhances the expression of a number pro-inflammatory cytokines, chemokines, immunostimulatory factors, and leukocyte-activation markers. A concomitant decrease in the expression of several genes associated with tumor growth, angiogenesis, and metastasis is observed after IL-12 therapy. At the cellular level, IL-12 treatment promotes the expansion, infiltration, and long-term maintenance of human leukocytes within the tumor microenvironment. Collectively, these data indicate that human TIL remain functional and responsive to cytokine stimulation in situ (i.e. within the tumor microenvironment), and are capable of mediating a suppression of tumor growth in vivo.