Modulation of Tumor Microenvironment by Nucleic Acid Chimeras as a New Paradigm for Adjuvant Cancer Therapy

It is known that tumor cells possess the capability to alter their microenvironment to facilitate the growth and invasion through modulating the immune responses. Several studies have indicated that the immune system is capable of eradicating tumor cells in most circumstances. However, tumor cells can secrete multiple types of cytokines and growth factors to manipulate the microenvironment by inducing inflammatory responses and suppressing the function of tumor-killing immune cells. Other than the tumor cells, tumor-associated macrophages (TAM) and regulatory T cells (Treg) are the two major cell types known to play key roles in regulating tumor microenvironment. Literature reports have indicated that reduction of these two cell types and the cytokines in favor of tumor growth will inhibit tumor progression significantly. We will study the cytokine gene expression profiles at different developmental phases of tumor progression in order to knock down the cytokines in favor of tumor progression and preserve the expression of the cytokines that inhibit tumor progression, for tumor mass with and without vascularization. The cytokine signaling pathways to be selectively silenced will be deciphered by DNA microarray expression profiling in order to identify the pivotal genes for knockdown. The advance of siRNA technology has proved that it is a powerful reagent for specific gene silencing. However, delivery of siRNA into specific target cells is still a great challenge. Toll-like receptor 2 (TLR2) is widely expressed in epithelial and myeloid lineage cells as well as carcinoma cells. In this study, we will start with TLR2 aptamer and NF-κB siRNA conjugate, the chimera, to silence the NF-κB expression in the tumor cells, TAMs, and Treg cells before the tumor mass is vascularized. After the tumor mass is vascularized, all kinds of immune cells enter the tumor microenvironment then aptamers specifically targeting to TAM and Treg cells will be used. Aptamers against specific TAM marker, FOLR2, and specific Treg marker, CTLA-4, will be developed to form chimeras with gene silencing siRNAs and serve to deliver the siRNAs specifically into TAM and Treg cells, respectively. The chimeras will selectively knock down the cytokine expression that facilitate tumor growth and create a microenvironment that is hostile to the tumor cells. Furthermore, we plan to combine the novel therapeutics with traditional therapeutic regimens to decrease the dosage and reduce the serious side effects of traditional therapeutics. This project is about developing a new therapeutic modality and platform technology. The successful implementation of the research aims not only will provide a new paradigm in cancer therapy. The principles behind the technology may be exploited for inflammatory diseases such as arthritis in the future.