The immune system plays a crucial role in various inflammatory disorders, tissue pathology, infections, diseases, and cancers. Thus, its regulation is often key to “curative” strategies. In this regard, Dr. Adeegbe’s research interests are primarily in the area of immune regulation and immunotherapy in the context of cancers. The focus is largely on the immune component of the tumor stroma and ways to manipulate it to achieve therapeutic endpoints. Therefore, studies in this lab entail both basic and translational studies, in order to better understand the immunological landscape of tumors and explore how emerging data can inform revision of existing therapies or in the design of new immunotherapeutic strategies.
Understanding and Overcoming Mechanisms of Response and Resistance to Immunotherapy
There has been a dramatic surge in interest and research efforts on immunotherapeutic approaches, such as α-PD-1 and α-CTLA-4 antibody therapy, for solid cancer in recent years, due to the remarkable durability in response observed in subsets of patients when benchmarked against targeted therapies involving small molecule inhibitors. Despite these promising outcomes, the question remains: why do some patients respond to immunotherapy but yet, others do not? In an attempt to tackle this question, we are utilizing mouse models of lung cancer and melanoma to conduct profiling studies in order to identify correlative patterns that segregate according to these outcomes. In addition, clinical specimens are being employed in parallel investigations, while findings from such profiling studies are integrated with clinical data. Knowledge of potential unifying signatures could inform not only mechanisms behind these differential responses, but could pave the way for design of new strategies to overcome incidence of drug resistance and broaden the therapeutic reach of immunotherapy.
Treg Immunobiology in Solid Cancers
It is well established that CD4+FOXP3+ Regulatory T Cells, or Tregs, account for a sizable pool of CD4+ T cells in many solid cancers. Given their developmental scheme and programming to ensure self-tolerance in the periphery, it is not surprising that Tregs accumulate in the tumor, where they are presumed to obstruct immune responses against tumor antigens that in most cases are self or altered self-antigens. How Tregs contribute to the immune dysfunction that is installed in most solid cancers remains to be fully understood. In this regard, one of the research foci in this lab is the understanding of the biology of Tregs in melanoma, lung, and prostate cancers. Through a comprehensive approach that encompasses cellular, molecular and genomic analyses, our lab seeks to understand mechanisms that underlie Treg evolution and function in these cancers. Studies in these directions are ultimately geared towards therapeutic strategies that are Treg-centric and would allow quantitative disruption or functional impairment of tumor, but not peripheral, Tregs.
Epigenetics-based Immune Modulation for Cancer Therapy
Epigenetic proteins regulate diverse aspects of tumor cell biology including proliferation, migration, cell survival, and apoptosis. Given their ubiquitous expression in tissues, there’s increasing appreciation for their roles in regulating hematopoietic cell behavior and function. This is particularly important in solid tumors where immune cells are a key component of the microenvironment. In recent studies, we have found that pharmacological inhibition of select epigenetics-regulating proteins can alter the phenotype and/or function of leukocyte subsets, which in turn impacts the course of tumor progression. Thus, another key focus of this lab is identifying promising agents that target select epigenetics-regulating proteins, and which have a positive immunomodulatory effect on tumor-associated immune cells while retaining deleterious effects on tumor cells. This research is conducted through in-vivo studies as well as in-vitro tumor propagation platforms. While emphasis is placed on dissecting the effects and associated mechanisms, by which select epigenetics-targeting agents evoke immunological changes in the tumors, of significant interest is also their use as rational partner drugs in novel combinatorial treatment strategies.