Eduardo Davila, PhD

My research team and I focus on achieving two main goals. First, we aim to develop novel approaches for treating established tumors by enhancing cytotoxic T cell responses towards weakly immunogenic and lowly expressed tumor antigens (TAgs).  Second, we focus on developing strategies to overcome the immunosuppressive tumor microenvironment (TME) to restore anti-tumor T cell responses.

T cell-based immunotherapies are arguably one of the most promising treatments for patients with advanced cancers. Several approaches that harness the T cell’s ability to destroy cancer cells include vaccine–based strategies, adoptive T cell transfer (ACT) of tumor infiltrating lymphocytes (TILs), T cells engineered to express tumor reactive T cell receptor (TCR), and ‘checkpoint blockade’ antibody (Ab)–based therapies. The results to various clinical trials have shown great promise and are achieving responses never seen before in various types of cancers including advanced melanoma. Despite these encouraging clinical results, durable antitumor responses are observed in only a small percentage of patients. This discrepancy stresses the need for developing more effective treatment strategies. 

T cell-based therapies are hindered in part by weak T cell activation. This is due to a variety of reasons including low TCR affinity and/or avidity as well as the suboptimal expression of tumor antigens on the cancer cell’s surface. Studies from several groups, including ours, have demonstrated that activating toll-like receptors (TLR)–MyD88 signaling in T cells can enhance tumor immunity. We have developed a novel strategy (consisting of a small synthetic protein) that activates MyD88 signaling in T cells in a strictly TLR-independent but tumor antigen-dependent manner resulting in the lowering the TCR activation threshold. We have also engineered T cells to deliver (and secrete) TLR ligands to the tumor site. The use of ‘T cell vehicles’ to transport immune adjuvants such as TLR ligands tends to re-shape the tumor environment towards one that favors tumor immunity. Our current efforts focus on understanding the molecular and cellular mechanisms by which MyD88–activated T cells lead to potent anti-tumor responses.

Through these studies, we have also come to appreciate that the development of effective and long-lasting anti-tumor T cell responses necessitates developing approaches to overcome a highly immunosuppressive TME. To this end, we are studying different methods to alter the TME to make it more immunogenic and/or to reduce the presence of immunosuppressive mechanisms with the ultimate goal of enhancing T cell responses. These approaches include combining T cell immunotherapy with radiotherapy (or focused ultrasound) or with targeted drugs in models of melanoma, glioma and pancreatic cancer. 

Another of our projects focuses on understanding how chronic inflammation contributes to tumor progression and tumor recurrence despite T cell therapy. We have found that certain tumor types such as melanoma and glioma exhibit a dysregulated inflammatory signaling pathway. Specifically, the IL-1 receptor associated kinase-4 (IRAK-4) is constitutively activated in these types of cancers resulting the chronic expression of various inflammatory and tumor growth factors. We have found that IRAK signaling in cancer cells promotes the generation of a suppressive TME by supporting the development of T cell-suppressive cells (i.e. myeloid derived suppressor cells; MDSC and tumor associated macrophages; TAM) and the expression of soluble factors that directly contribute to T cell dysfunction.

Our studies are conducted in collaboration with various UMGCCC basic and clinical research investigators. Working together, we aim to better understand the immune regulation of malignant disease and focus on translating this knowledge into developing novel diagnostic, preventative and treatment regimens. A list of ongoing cancer immunotherapy trials can be found here.

Finally, mentoring and guiding students towards successful careers in science is an important component of being a scientist. We recently initiated the STAR-PREP, a 1-to 2-year mentored postbaccalaureate research training program designed to prepare recent baccalaureate graduates for successful entry into Ph.D. or M.D./Ph.D. programs. This program caters to highly ambitious and motivated students, who recently received their bachelor’s degree (or who are in their senior year) and are interested in pursuing a Ph.D. in biomedical sciences.