Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death, according to the American Cancer society. Therapeutic efficacy of cancer treatment, including cancer immunotherapy, certain chemotherapy, and radioactive therapy, requires the immune system, specifically effector T cells. These T cells mediate potent anti-tumor immunity. However, successful cancer therapy requires efficient trafficking of the T cells into the relevant tumor site. This problem is especially apparent in solid tumors including colon cancer, where the tumor creates a block to prevent T cells from entering. The proposed work is seeking to understand this block: the repressive machinery involved in limiting T cell trafficking into the tumor. The final effort is to target the machinery with a pharmacological drug to improve antitumor immunity. The drug target and repressive machinery involves epigenetic regulation, a form of regulation beyond the DNA code itself that can repress and turn on genes. The regulation is reversible and a good target for pharmacological drugs. This project is designed to apply molecular immunobiology to translational research, as the project is carried out in human-derived samples/tissues with the latest technologies and developments in the field of epigenetics. Various molecular and cellular immunobiology techniques will be used, alongside mouse models and samples from cancer patients, to address the mechanism of action and therapeutic relevance, respectively. Consequently, this proposal will allow for the unique training of an independent scientist through increasing scientific knowledge in many fields (immunology, cancer biology, and epigenetics), both technically and theoretically. Thus, the goals are aligned with those of the NCI and NRSA, as the proposed research involves understanding mechanisms of tumor progression and cancer therapy and contributing to the betterment of society by inspiring and educating our future leaders in science.
Therapeutic efficacy of cancer treatment, including cancer immunotherapy, certain chemotherapy, and radioactive therapy, requires the immune system, specifically effector T cells;these T cells mediate potent antitumor immunity. However, the tumor (to its advantage) creates a block to prevent these T cells from entering, which is especially apparent in solid tumors including colon cancer. The proposed work is seeking to understand, in human colon cancer, how to increase effector T cell trafficking into the tumor in an effort to dramatically increase these powerful T cells in the tumor and thus antitumor immunity.
|Nagarsheth, Nisha; Wicha, Max S; Zou, Weiping (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17:559-572|
|Nagarsheth, Nisha; Peng, Dongjun; Kryczek, Ilona et al. (2016) PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. Cancer Res 76:275-82|
|Peng, Dongjun; Kryczek, Ilona; Nagarsheth, Nisha et al. (2015) Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527:249-53|