My investigations are designed to identify the mechanisms whereby cell extrinsic signals; antigen, co-stimulation and cytokines, are integrated to regulate metabolism and/or transcription that determine the fate of antigen specific CD8+ T cells. The fundamental insights obtained are applied to the development of new immunization and adoptive cell transfer (ACT) approaches for durable tumor immunity. The laboratory employs several murine tumor models including Ovarian, Melanoma, Glioblastoma, Breast and Lung, these models were chosen based on the different T cell tolerance mechanisms observed so that different approaches to overcome tolerance can be tested and validated for translation. One of the many fundamental insights we have obtained by employing combinatorial approaches of a reductionist approach for understanding T cell biology and murine tumor model systems is the critical role played by the energy sensitive kinase; mTORC1, in integrating cell extrinsic signal 1 (Antigen), signal 2 (co-stimulatory molecules; B7.1, 4-1BB or CD40, and signal 3 (cytokines; IL-12, IL-21), to program naïve CD8+ T cells for effector and/or memory fates. Since, we and other have demonstrated a role for mTORC1/2 in the regulation of transcriptional and metabolic programs, we are continuing to explore the interplay between metabolism and transcription that establishes a variety of memory fate sin antigen stimulated CD8+ T cells. The concepts for the art of producing memory T cells and employ them for cancer immunity has been patented and is being applied for ACT of cancer in several multi-institutional phase 1 clinical trials. In another project, we are characterizing mechanisms by which TCR induced NFKB is regulated for effector versus memory differentiation and the role epigenetic modifiers; KDAC’s, play in programming CD8+ T cell fate. Collectively, insights obtained from these basic investigations are applied to the clinical setting and several new phase1 clinical trials are underway in collaboration with Dr. K. Odunsi (RPCI), Dr. W. Gillanders (Wash. U) and Dr. C. Yee (MD Anderson). Recently, we have formed a consortium among scientists in Arizona (UofA-Tucson, ASU, UofA-PHX, Mayo Clinic, NAU and TGen) with a common goal to eradicate Ovarian Cancer. This group plans to build a platform for a future program project encompassing the various expertise including, Inflammation, Microbiome, Imaging, Oncolytic viral therapy, innate-T cell communication, autoimmunity and durable immunity. The bench to bedside to bench paradigm is actively practiced in our laboratory, resulting in several patents, high impact publications and Investigational New Drug (IND) based Phase 1/2a clinical trials. The broad scope of investigations serves as a useful platform to train future basic/translational/clinician scientists.
