Title: Balancing oncogenic inflammation and anti-tumor immunity in the development of novel immune therapies for cancer
Description: Immune therapy is already established as a central component of many cancer treatment regimens, employing a variety of manipulations to activate anti-tumor immunity. The goals of tumor immunology are to elucidate the molecular and cellular interactions between tumors and the immune system, and to develop novel strategies for eliciting protective anti-tumor immunity in patients. Here we present data exploring two distinct, but related aspects of cancer immunology: the relationship between the immune system and tumor development, and mechanisms for augmenting immunity to established cancers. Lung cancer is the leading cause of cancer death worldwide. Although both principal factors known to cause lung cancer, cigarette smoke and asbestos, induce pulmonary inflammation, the importance of inflammation in lung cancer is unclear. We have generated immunodeficient mice that develop pulmonary inflammation and high frequency lung tumors due to combined loss of interferon (IFN)-γ, and the β-common cytokines granulocyte macrophage colony stimulating factor (GM-CSF) and IL-3. Tumors in this model occur in the context of chronic inflammation and infection, and we find that the cytokine IL-6 drives their growth; however, these tumors can also be rejected when transplanted into wild-type animals, indicating roles for both the loss of anti-tumor immunity and tumor-promoting inflammation in this system.

The complexity of the interaction between tumors and immune cells often necessitates combination therapy to generate protective anti-tumor immunity. The inhibitor of apoptosis proteins (IAPs) are highly expressed in tumor cells, and, in pre-clinical models, the IAPs have been effectively targeted by a novel class of cancer chemotherapeutics. Here we show that the IAPs act as negative immune regulators in addition to their role in tumor apoptosis. IAP antagonism augments mouse and human T cell stimulation in vitro, leading to enhanced cytokine production, proliferation, and expression of activation markers. This effect resembles co-stimulation, and requires blockade of IAP-mediated inhibition of alternative nuclear factor (NF)-κB signaling. We further show that IAP antagonism blocks NKT cell development, and augments the function of B cells, dendritic cells, and natural killer cells; finally, IAP antagonists can be delivered systemically to enhance anti-tumor responses following vaccination.