Erapa-Mediated T Cell Effects in Intestinal Neoplasia

Cancer is the leading cause of death worldwide. In the US, it claims more lives in Americans younger than 85 years of age compared to any other cause. As a nation, hundreds of billions of dollars are spent annually on cancer research and care, but cancer death rates have not changed significantly for most advanced-stage cancers. These grim statistics point to a need for novel and effective cancer prevention strategies, as prevention can be more clinically effective and is clearly more cost effective than most cancer treatment strategies. A landmark study from our collaborators in 2009 found that a novel enteric formulation of rapamycin (eRapa) prolonged survival in normal mice and follow-up studies suggested cancer delay or prevention as a mechanism for eRapa's longevity extension properties. In the ApcMin/+ mouse model of intestinal neoplasia, our preliminary data established that eRapa extends lifespan of ApcMin/+ mice by reducing their intestinal tumors, consistent with the role of eRapa in delaying or preventing cancer. Rapamycin and its analogs are currently being studied as possible cancer therapeutic agents, including in human clinical trials, but there has been relatively little focus on its use as a cancer prevention agent. Also litle studied are rapamycin's significant immune modulating effects in cancer treatment or prevention. Cancer immune surveillance is a normal endogenous mechanism that helps to prevent cancer from becoming clinically apparent. T cells are critical modulators of this surveillance mechanism. Our preliminary data in normal mice show that eRapa boosts T cell effects generally favorable to cancer immune surveillance while diminishing unfavorable suppressive T cell effects, but these findings have yet to be proven mechanistically in a tumor setting. Thus ApcMin/+ mice will be used to test our main hypothesis that eRapa-mediated T cell effects in intestinal neoplasia contribute to cancer prevention through enhanced cancer immune surveillance. This main hypothesis will be addressed through the following specific aims: (1) test the hypothesis that eRapa reduces spontaneous intestinal neoplasia by boosting T cell immunity and/or (2) by mitigating tumor-associated T cell dysfunction, and (3) test the hypothesis that eRapa reduces inflammation-driven intestinal neoplasia through immune effects. To address specific aims 1-2, parental ApcMin/+ mice and various cytokine and T cell knockout ApcMin/+ mice will be given eRapa for a defined amount of time and sacrificed to study intestinal tumor formation and effects on specific T cell properties (e.g., cytokine production, Th differentiation, expression of immune suppressive factors). Additionally, in vitro systems will be utilized to generate specific myeloid cell subsets to study eRapa's effects on T cell differentiation pathways as a way to confirm in vivo results. To address specific aim 3, ApcMin/+ mice will be challenged with the inflammatory agent, dextran sodium sulfate, to induce malignant tumor degeneration. Then survival and similar T cell properties as in aims 1-2 will be assessed to elucidate mechanisms of eRapa-mediated clinical effects. These proposed studies are significant because they will support the use of rapamycin and its analogs as potential first-in-class cancer prevention agents. PUBLIC HEALTH RELEVANCE: Cancer is the leading cause of death worldwide and the number two killer in the United States. Thus, strategies to combat or prevent cancer are needed to curb this growing public health problem. These studies will support the use of rapamycin and other mTOR inhibitors as potential cancer prevention agents.