The central theme of the Shanker laboratory is to understand the molecular basis of functional crosstalk between the innate and adaptive lymphocytes, with a particular focus on preventing immune escape of solid tumors. Dr. Shanker’s pioneering studies in murine tumor models identified that tumor-infiltrating CD8T cells provide a necessary “help” to dormant intratumoral natural killer (NK) cells in eliciting their antitumor effector function. CD8T and NK cell interaction results in an altered phosphorylation of multiple signaling proteins and mitochondrial Ca2+ dynamics, suggesting a cellular remodeling allowing acquisition of NK cell effector/regulatory and T cell central memory phenotypes. This lymphocyte cooperativity led to complete regression of tumors, including their antigen-escape variants.

Interestingly, analysis of lymphocytes from breast cancer patients showed that signatures of NK cell activation predicted relapse-free survival post initial surgery. Our translational efforts are, thus, invested in optimizing antitumor crosstalk of adoptively transferred CD8T and NK cells by various lymphocyte-stimulatory strategies including the proteasome inhibitor bortezomib, Notch ligand clusters, and neurotransmitters. Our approach integrates various genetic manipulations, cellular and molecular tools, intravital bioluminescence imaging, and analyses of immune function in a whole animal model. Recently, we showed that bortezomib treatment in mice bearing breast and kidney tumors provided host survival benefit by amplifying tumor cell caspase8 activation, CD8T cell effector molecules via increased NotchNFkB crosstalk and Fas ligandmediated lysis of tumor cells. Working with lung cancer models including EGFR-resistant inducible lung cancer, we showed that Notch stimulation in CD8T cells by Delta-like Notch ligand DLL1 multivalent cluster enhances their antitumor function and memory. Dr. Shanker’s expertise, leadership, and motivation to structure and direct the current research will uncover underlying mechanisms of lymphocyte crosstalk, along with their interface with neural signaling. This work of cross-disciplinary impact would advance our understanding of lymphocyte processes, help design effective combinatorial immune strategies that strengthen lymphocyte function and overcome cancer-associated immunosuppression, and could identify immunogenetic signatures to explain the cancer health disparities observed in various ethnicities.

Dr. Shanker is the Coordinator of Cancer Immunotherapy program at Meharry Medical College, and a member of the Vanderbilt-Ingram Cancer Center as well as the Vanderbilt Center for Immunobiology & Translational and Clinical Immunology. He actively participates in the Host-Tumor Interactions and Tumor Immunology programs. Last year, he co-organized the “Advances in Cancer Immunotherapy” course sponsored by the Society for Immunotherapy of Cancer at Vanderbilt University. The Shanker laboratory has provided a vibrant research and teaching environment for over 35 undergraduate, doctoral, postdoctoral and medical trainees, who are actively contributing in the field.