Three specific targets of Dr. Edwards' research include: 1) vaccine therapies for cervical and ovarian cancer; 2) combining biologic and immunologic therapies with traditional therapies in the treatment of women's cancer; and 3) intraperitoneal therapy.
In recent years, the decades-long promise of tumor immunotherapy has finally begun to come to fruition. Checkpoint blockade, for example, represents a critically important intervention for potentiating the antitumor immune response. In these therapies, blockade of T cell intrinsic negative regulators (such as CTLA-4 and PD-1 signaling) releases the brake on effector T cells in the tumor, resulting in substantial, durable antitumor immunity, and clinical responses.
While negative regulators on the effector T cells can be relieved through these interventions, effector T cells still face a variety of cell extrinsic modes of immune suppression, notably through suppression via regulatory T (Treg) cells. Treg cells play critical roles in preventing autoimmune responses to self tissues as well as limiting immunopathology during exuberant immune responses. However, Treg cells represent a major barrier to antitumor immunity. Many tumors recruit, activate, and expand large numbers of Treg cells, which can be specific for any number of normal, self antigens expressed by the tumor. While depletion of total Treg cells can result in autoimmune pathologies, inhibition of Treg cell stability or function has been shown to allow for local inhibition of Treg cell suppression in the tumor, while sparing normal tissues from an autoimmune response.
Thus, finding phenotypic, signaling, or functional parameters that distinguish intratumoral Treg and conventional T (Tconv) cells could shed light on mechanisms by which Treg cells could be targeted to allow for a greater antitumor response. Recent studies have found that Tconv and Treg cells have distinct metabolic requirements. Not unlike cancer cells, conventional T cells undergo aerobic glycolysis (the 'Warburg effect') when undergoing robust expansion. However, regulatory T cells utilize alternative sources of fuel. Our initial findings in the laboratory suggest that not only do intratumoral Treg cells utilize distinct fuel from their conventional brethren, but engage different metabolic pathways from Treg cells in normal tissues and lymphoid organs. This suggests that metabolic pathways, or their downstream targets, could be targeted in order to inhibit intratumoral Treg cells specifically, releasing a crucial cell extrinsic brake on the antitumor immune response. The goal is to provide alternative modalities of therapy that could be utilized alone or in combination with other immunotherapeutic strategies, to allow for robust and durable immune responses for the eradication of cancer.
Dr. Ferris's laboratory is focused on understanding basic immunological mechanisms of the T lymphocyte response to cancer, for the development of novel immunotherapeutic approaches to head and neck cancers (HNC). Tumor vaccine clinical trials are currently underway and new strategies are in development. We are particularly interested in the immune response to human papillomavirus (HPV)-associated head and neck cancer, which appears to be a distinct subgroup of head and neck squamous cell carcinomas. Monitoring the successful immune effects of individuals treated with immunotherapy is a major effort, in order to develop improved generations of vaccine approaches. We are also studying tumor induced immune evasion, such as defective antigen processing and presentation to subvert cytotoxic T lymphocyte recognition of tumors.
Another area of study involves the promotion of tumor metastasis by a family of molecules called chemokines. We are finding important roles for chemokine receptors in cancer metastasis. These chemokines are small, secreted molecules that mediate homing and recruitment of immune cells in response to inflammation, through a family of G-protein linked receptors. Overall, these studies are designed to identify the chemokines relevant to progression of HNC and to provide initial data on their possible clinical utility as components of future vaccination therapies for HNC. In addition, our group is interested in developing immune/inflammatory biomarkers present in the bloodstream for HNC detection, and monitoring in populations at risk for cancer recurrence and/or second primary tumors.