The Shanker laboratory studies information processing and signal transduction circuitry underlying lymphocyte crosstalk in response to pathological conditions. In the tumor microenvironment of murine solid tumors that express cancer-germline self-antigen P1A (J Immunol 172:5069), our pioneering studies discovered a new paradigm of CD8 T cell help for innate effector function that potentiates immunosurveillance against tumor development and antigen escape (J Immunol 179:6377). Our ongoing workhas identified mitochondrial Ca2+transport-mediated intermembranous exchange and Notch–NFkB signaling crosstalk as key mechanisms guiding CD8+T–NK cooperativity. These findings provide for novel immunotherapy approaches that we are exploring to prevent tumor development and escape. In breast, kidney and inducible EGFR-mutant lung cancer mouse models, and patient samples from a multi-institutional collaboration, we are testing various adoptive transfer protocols of CD8+T and NK cells in combination with immunomodulatory agents such as engineered multivalent NOTCH ligand clusters (Cancer Res 71:6122; 75:4728; JITC 7:95), bortezomib, a proteasome inhibitor (J Immunol 180:163; JNCI 100:649; Cancer Res 75:5260), and neurotransmitter agonists. Currently, we are performing a comprehensive analysis of NOTCH signaling and associated metabolic, effector and memory gene expression patterns in lymphocytes from preclinical animal models and NSCLC patient samples. The outcomes would provide novel prognostic biomarkers and immunologic basis of health disparities in cancer and other pathological disorders.