Immune suppressive pathways in cancer: mechanism and applications

© 2013 Dr. Shin Foong NgiowThis thesis elucidates a number of topical studies in the field of tumor immunology, with a particular focus on three immunosuppressive pathways. These include the Foxp3+ regulatory T cells, a T cell checkpoint protein named T cell immunoglobulin and mucin domain 3 (Tim-3), and a pro-inflammatory cytokine interleukin-23. The assessment of these immunosuppressive pathways was performed in vivo, using a broad spectrum of experimental and de novo tumorigenesis models, to illustrate their biological importance in modulating tumor growth. In cancer immunotherapy, the risk of autoimmunity needs to be weighed against the anti-tumor benefits. In Chapter 3, by using a transgenic mouse model to conditionally and specifically deplete Foxp3+ regulatory T cells in the poorly immunogenic B16F10 melanoma model, an enhanced anti-tumor response was observed. In addition to modulating the surface immunogenicity of tumor cells, the enhanced anti-tumor response also induced autoimmune vitiligo in tumor-bearing mice with a specific tumor growth profile. This study revealed the importance of a rapid and effective anti-tumor response in dissociating potential autoimmunity development in the host. Next, in Chapter 4, an anti-Tim-3 mAb was shown to suppress established tumor growth in multiple tumor models. The tumor suppression effect of anti-Tim-3 mAb was shown to be mediated by host T cells and interferon-γ. Notably, when anti-Tim-3 mAb was used in combination with other T cell checkpoint inhibitors, a synergistic antitumor response was observed. Despite the increased strength of anti-tumor immunity, tumor-bearing mice were not more susceptible to the development of any overt autoimmunity. These findings support the use of a combination of T cell checkpoint inhibitors to treat cancers. As an extension of Chapter 4, in Chapter 5, it was demonstrated that Tim-3+ regulatory T cells were enriched in the tumor microenvironment, but not in other lymphoid organs. Tim-3+ regulatory T cells were shown to be potent producer of interleukin-10. More interestingly, the presence of Tim-3+ regulatory T cells was demonstrated to limit the expansion, and to promote the exhausted phenotype, of effector T cells. Collectively, these findings position intratumoral Tim-3 as a unique immunotherapy target in cancer. Finally, in Chapter 6, the tumor-promoting or -suppressing role of interleukin-23 was explored using mice mutant for p53 or gamma-irradiated. In contrast to inflammation-driven tumorigenesis models, the absence of IL-23 did not modulate the survival of tumor-bearing mice in the aforementioned settings. This may suggest that interleukin-23 drives tumorigenesis in an inflammation-dependent manner. In this Chapter, together with the assessment of two cytokines downstream of interleukin-23, it is demonstrated that the interleukin-23 inflammation axis modulates tumorigenesis in a highly context-dependent manner. Overall, the findings presented in this thesis contribute towards a better understanding of the complexity of immunosuppressive machineries that facilitate tumorigenesis