Modification of tumor micro-environment to enhance anti-tumor immune response.

다국어 초록 (Multilingual Abstract)

Increasing attention have been generated to minimized the adverse immune impact of tumor infiltrated myeloid cells to increase the anti-tumor immune response and potentially enhance tumor control. In present study, we've demonstrated that intratumorally administration of a peptide based vaccine in well defined solid tumor combining PADRE peptide and poly I:C leads to an enhanced antitumor effects in treated mice comparing with conventional vaccine route giving subcutaneous (Chapter 2). This challenges the prevailing notion of the tumor as an inherently immune-suppressive site and underscores the dynamic nature of interactions between the tumor and the immune system. Also, we evaluate the phenotype change of macrophages in the peritoneal cavity of disseminated ovarian cancer model after poly I:C treatment. With the help of PEI to increase the uptake of poly I:C by the peritoneal cells, significant improvement was observed in the antitumor effects against murine ovarian tumors. This anti-tumor effect was contributed by the alternative MI activation of peritoneal macrophages when treated and sequentially activate NK cells to clear tumor (Chapter 3). This suggests that the environment of ill-define disseminated tumors can also be changed to significantly benefit tumor control. Last, we focus on how conventional cancer treatments, tumor irradiation impact the tumor microenvironment. In chapter 4, we've show that by combining RT and targeted delivery of antigenic peptide to the tumor, the adjuvant effect generated by RT itself is sufficient to elicit the priming and expansion of antigen-specific CD8+ T cells through the type 1 interferon and toll like receptor 4 dependent pathways and leads to a potent therapeutic antitumor effect. In addition, we demonstrated that CTL-mediated killing of CD11b+ myeloid stromal cells, in the tumor by our approach is important for the control of tumor growth using two different transgenic mouse models. Altogether, we observed a greater tumor control achieved through the suppression of the immunomodulatory effects and the enhancement of favorable immune stimulation due to local RT. In summary, these results demonstrate that the immune-suppressive tumor micro-environment can be reversed by available, commonly practiced, interventions and provide impetus for the development and clinical translation of novel immune-based strategies for cancer therapy.
iii.