Drug resistance has limited the efficacy of almost all anti-cancer therapeutic agents. Although recently several anti-cancer agents such as immune checkpoint inhibitors (such as anti-PD-1, anti-CTLA4), co-stimulatory agonists (such as anti-OX40, anti-GITR) and small molecule inhibitors of various kinases (such as PI3K, AKT, MAPK) and their combinations have been developed, they are typically associated with recurrence due to development of resistance during the course of treatment. Recently, we have found that the sequencing, scheduling and dosing of these agents is of paramount importance for therapeutic outcomes. In our lab, we delineate mechanisms of primary (innate) and secondary (acquired) resistance to these immune modulators to achieve durable responses to therapy.

Recently, cancer immunotherapy including monoclonal antibodies blocking the inhibitory immune checkpoints and targeted therapies using small molecule inhibitors have made a significant impact on the treatment of cancer patients. However, majority of the patients fail monotherapies making it clear that they are not sufficiently active on their own. Recently, we and others have shown that combining immune modulating monoclonal antibodies with other immune modulators such as radiation therapy, chemotherapy and small molecule inhibitors has the potential to further enhance the clinical benefits of monotherapies. Based on the synergistic mechanisms of various therapeutics, in our lab we are working to identify and prioritize the most promising combinatorial approaches as well as identify the underlying mechanisms of failure or success of the combination.

Bidirectional interaction between various cells in the tumor micro-environment (TME) is a decisive factor for therapeutic outcome as they regulate tumor growth and immune suppressive milieu of the TME. Tumor associated immune suppressor cells such as Tregs, MDSC and IDO-expressing cells can effectively block anti-tumor immune responses, thereby representing an important obstacle for immunotherapy. Consequently, there has been considerable interest in developing approaches that can selectively or preferentially target these cells. In our lab, we are investigating the anti-tumor effects of various agents that expand the effector cells while deplete/inhibit suppressive cells. In addition, we are evaluating the role of epigenetic modifications and mechanisms underlying the recruitment, expansion, and suppressive activity of these cells.

T-cell plasticity is crucial for their ability to adapt to the ever changing TME. Upon antigen stimulation, small and quiescent naïve T-cells undergo activation and proliferation and subsequently differentiate into distinctive functional subgroups that are essential for appropriate immune response and regulation. In our lab, we are delineating the role of various pathways including PI3K/Akt and Ras/Raf/MAPK in cell plasticity so that various agonists or antagonists of these pathways can be used for generation of appropriate cell lineage required for specific immune response. Furthermore, the metabolic reprogramming and lymphocyte activation are closely interconnected. To meet the the demands of increased cell proliferation and change in cell phenotype (naïve vs effector vs memory) the lymphocytes must adapt to the changing environmental conditions. Although recently several studies have shown the importance of cell metabolism in deciding their anti-tumor activity, the effects of various anti-cancer agents including monoclonal antibodies and small molecule inhibitors remain poorly understood that acts a barrier in developing effective cancer therapies. In our lab, we are investigating the effects of cancer immunotherapeutics such as MEk inhibitors on the metabolic reprogramming in effector T-cells and their fate and function. In addition, we are studying the effects of multiple natural compounds such as Vitamin C and Selenium on the reprogramming of T-cells.