The contribution of regulatory T cell subsets to tumor development.

The tumor microenvironment is highly immunosuppressive, representing one of the common hurdles that prevent an effective approach to cancer immunotherapy. Regulatory T cells (Tregs) are critical initiators and amplifiers of the immunosuppression. Not only do they directly repress effector cells that attack the tumor, but they are also expanded by the other suppressors – such as myeloid derived suppressor cells (MDSC) and tumor associated macrophages (TAM) – to intensify the immunosuppression and to enhance tumor growth. The identity, stability, and function of Tregs within the tumor remain largely unclear. We will a) characterize Treg cell subsets within the tumor microenvironment; b) evaluate approaches to modify these Treg cell subsets to induce enhanced antitumor immunity.

The contribution of NK cell subsets to antitumor responses.

Current efforts in immunotherapy have focused mainly on enhancing T-cell responses to tumors. Less is discussed regarding how to mobilize other effector cells, such as NK cells, to mediate cooperative antitumor responses. Although NK cells, a component of innate immunity, are endowed with tumor-killing activity, and often correlate with the prognosis of cancer patients, relatively limited insight into NK cell biology has impeded NK cell–based therapeutic approaches. We will a) delineate the contribution of genetic and epigenetic regulation to NK cell function and to NK cell adaptive responses; b) characterize NK cell adaptive responses to tumors and evaluate approaches that can enhance such responses.

The impact of oncolytic HSV-based therapy on antitumor immune responses.

This is a collaborative project among immunologists, neurologists and neurosurgeons at UAB. Using mouse models and specimens from patients with malignant brain tumors pre- and post-treatment with a replication conditional oncolytic HSV (oHSV), we will characterize the impact of oHSV therapy on the immune responses systemically and within the tumor, to seek biomarkers for the improved outcome and design combined approaches to enhance antitumor responses.