Treg-Th17 Axis Modulation and Induction of Tumor Immunity with Cryosurgery

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DESCRIPTION (provided by applicant): Cancer is a difficult disease to treat due to its destructive nature. This is especially true in the aging population, where patients cannot tolerate more aggressive therapies, such as invasive surgery and chemotherapy regimens. Alternatively, cryosurgery, the use of freezing temperatures to destroy diseased tissue, is increasingly recognized as an efficient, minimally invasive method of treating solid tumors. Compared to surgical resection, cryosurgery is less damaging to surrounding structures, places less stress on the body, has improved patient comfort, is more affordable, and provides a better cosmetic result. More importantly, cryosurgery has the potential to induce an immunologic response to tumor-associated antigens, which are released from the ablated tumor. Not only is this immune response able to prevent tumor recurrence in patients but it is also capable of eliminating distant metastatic foci. However the mechanisms by which cryoablation induces anti-tumor immunity have yet to be elucidated. The goal of this project is to resolve these mechanisms by studying the interaction between the immune regulatory system and cryoablation. This project will focus on the immune inhibitory (T regulatory cells) and pro-inflammatory (Th17 cells) axis that exists within the immune system. This axis can be shifted from one spectrum to the other creating a variety of immune inhibitory or stimulatory environments. Our preliminary data have shown that cryoablation increases both T regulatory (Treg) and Th17 populations, indicating that the Treg-Th17 axis has a significant role after cryosurgery. We hypothesize that a shift in this axis towards the pro-inflammatory spectrum (Th17 cells) will allow immune effectors to overcome self tolerance and induce long term anti-tumor immunity. To test this hypothesis we propose the following aims: 1) Characterize the kinetics of T-cell activation and cytokine profiles in mice after cryosurgery to determine the shifts in the Treg-Th17 axis, 2) Alter the mouse immune environment to favor Th17 response in coordination with cryosurgery, and 3) Evaluate anti-tumor activity when DNA vaccination and cryosurgery are combined. PUBLIC HEALTH RELEVANCE: The goal is to eliminate the solid tumor mass by cryosurgery and release all tumor-associated antigens to boost anti-tumor immune response. A less invasive procedure, cryosurgery may be advantageous for senior patients who are not able to endure harsh treatment options. To facilitate the activation of effectors, rather than suppressive T cells following cryotherapy, I will test the hypothesis that inducing a shift from the regulatory T cells toward IL-17 producing T cells before cryosurgery by intratumoral expression of IL-6 will favor anti-tumor immune response. Furthermore, systemic immunization with DNA vaccine will be tested to compliment cryosurgery. Results from this study could significantly advance cancer treatment, especially in senior patients.