Shikhar Mehrotra, Ph.D.

The goal of my lab is to develop strategies for improving immunotherapy of melanoma by focusing on the following aims: i) To orchestrate a robust and long-lived Tumor Antigen Associated Cytolytic T Cell (CTL) response; ii) To engineer T cells expressing tumor epitope-specific T Cell Receptor (TCR); and iii) To determine the strength of TCR receptor signaling in deciding the fate of CTL’s towards life or death. Another focus of my lab is to understand the role of autoimmune T cells in the development of vitiligo. My research group has dissected several signaling and metabolic pathways that could be exploited to generate robust anti-tumor T cells. Previously we showed that effector T cells can be demarcated based on cell surface thiol (c-SH) expression into c-SHhi and c-SHlo T cells. They showed that high anti-oxidant property is central to potent anti-tumor effector T cells, and directly correlates to CD62Lhi central memory, low glycolytic, and low mitochondrial membrane potential phenotype, all of which may be linked and contribute to better tumor control. My group has also shown that p53 regulates T cell glycolysis and altering p53 levels in T cells could be exploited to control tumor growth. More recently, we generated a long-lived anti-tumor response by targeting the expression of ectonucleotidase CD38 on effector T cells by developing novel ex vivo programming conditions that result in Th1/17 hybrid signature and a concomitantly reduces the expression of canonical (CD39, CD73) and non-canonical ectonucleotidases (CD38). Since CD38 is not only involved in the generation of suppressive adenosine (along with CD39, CD73, and CD157), it is also a NADase, i.e., degrades nicotinamide adenine dinucleotide (NAD). Since NAD is an important regulator of mitochondrial metabolism, and also acts as a substrate for histone deacetylase Sirt family of proteins, we were able to show that that inhibition of CD38 expression or rendering T cells with hybrid phenotype leads to increased or maintenance of NAD+ levels in a T cell, which in turn will result in metabolically fit T cells with the ability to control tumor growth long-term and also contribute to the generation of tumor-specific memory T cells (Cell Metabolism, 2018). We have also been able to translate these bench-side observations to get FDA approval for a clinical trial to use “Metabolically Fit CD19 CAR T-cell Therapy With CD34 Selection in Patients With CD19+ Relapsed/Refractory NHL, CLL/SLL”, ClinicalTrials.gov Identifier: NCT05702853.