Shikhar Mehrotra Ph.D. Research Laboratory

Shikhar Mehrotra, Ph.D., co-scientific director of the CCT, focuses his translational research on understanding T cell biology for improving immunotherapy for cancer. When it comes to treating cancer, cellular therapy is the next frontier. A new clinical trial (ClinicalTrials.gov identifier: NCT05702853) recently opened for recruitment, where patients’ T cells are engineered with CD19 Chimeric Antigen Receptors (CARs) and modified to make them “metabolically fit,” and increase efficacy while reducing toxicity. Similar strategies are being pursued using NCI STTR R41 and R42 funds to generate validation data for new clinical trials that will use tumor-infiltrating lymphocytes (TILs) to treat people with malignant melanoma, breast cancer, and prostate cancer.

In order to generate tumor reactive T cells that can persist longer, and lead to control of tumor growth, the Mehrotra lab is testing several strategies by understanding the overlap that exists between the immune cell signaling pathways and cellular metabolic state associated with it. They previously described a novel strategy to demarcate effector T cells based on cell surface thiol (c-SH) expression into c-SHhi and c-SHlo T cells. They showed high anti-oxidant property is central to potent anti-tumor effector T cells, and directly correlates to CD62Lhi central memory (Tcm), low glycolytic and low mitochondrial membrane potential phenotype, all of which may be linked and contribute to better tumor control. These studies were extended to show the role of thiol regulating molecule thioredoxin in maintaining Tcm phenotype. His 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, his group has shown that targeting non-canonical ectonucleotidase CD38 on T cells could lead to a potent and long-term control of tumor mediated by anti-tumor T cells by maintaining higher levels of NAD+ (a cofactor and substrate for various post-translational modifications). His group is also working to combine strategies where targeting kinases with checkpoint blockade could enhance effectiveness of ACT. Another study from his group showed that PIM kinase inhibition leads to drop in glycolysis and maintenance of Tcm phenotype. Further, a combination of PIM kinase inhibitor administered along with anti-PD1 and ACT leads to a robust tumor control. Thus, the overall goal remains to translate the novel pre-clinical approaches targeting immuno-metabolism to clinics for improving the outcomes of T cell based immunotherapy trials.

About Dr. Mehrotra

Dr. Mehrotra competed his Ph.D. in Immunology in India and post-doctoral fellowship at University of Connecticut Health Center in Farmington, CT. He moved to Medical University of South Carolina (MUSC) in Charleston in 2006, where his research group has focused on understanding T cell biology for improving immunotherapy of cancer. Dr. Mehrotra is also the Scientific Director of the FACT accredited Clean Cell Therapy Unit at MUSC. In 2020, Shikhar Mehrotra, Ph.D., was selected to serve on the College of Medicine’s Research Oversight Committee. The Research Oversight Committee was formed to provide strategic and operational guidance. Dr. Mehrotra serves as one of the charter members of this newly-formed committee.

Selected Publications

Pro-survival Lipid Sphingosine-1-Phosphate Metabolically Programs T cell to Limit its Anti-Tumor Activity. Cell Reports 2019; 28: 1879-1893. Chakraborty P, Vaena SG, Thyagarajan K, Chatterjee S, Al-Khami A, Selvam SP, Nguyen H, Kang I, Wyatt MW, Baliga U, Hedley Z, Ngang RN, Guo B, Beeson GC, Husain S, Paulos CM, BeesonCC, Zilliox MJ, Hill EG, Mehrotra M, Yu XZ, Ogretmen B, MehrotraS.
CD38-NAD+ Axis Regulates Potent Immunotherapeutic Anti-Tumor T cell Response. Cell Metabolism, 2018;27:85-100. Chatterjee S, Thyagarajan K, Kesarwani P, Song JH, Soloshchenko M, Fu J, Bailey SR, Vasu C, Kraft AS, Chatterjee S, Daenthanasanmak A, Chakraborty P, Meek M, DharP, Paneerselvam S, Nygen H, Toth K, Al-Homrani M, Zhang J, MehrotraM, Ball L, Beeson G, Husain S, Garrett-Mayer E, Hardiman G, Nishimura MI, Beeson CC, Gubbels-Bupp M, Wu J, OgretmenB, Paulos CM, Rathmell J, Yu XZ, Mehrotra S.
Reduced CD73 Expression by TGF-β Independent Th17 Cells Improves Tumor Control. Cancer Research 2014; 74: 6048-59. Chatterjee S, Thyagarajan K, Kesarwani P, Song JH, Soloshchenko M, Fu J, Bailey S, Kraft AS, Vasu C, Paulos CM, Yu XZ, Mehrotra S.
Promoting thiol expression increases the durability of antitumor T-cell functions. Cancer Research 2014; 74(21):6036-47. Chatterjee S, Thyagarajan K, Kesarwani P, Song JH, Soloshchenko M, Fu J, Bailey S, Kraft AS, Vasu C, Paulos CM, Yu XZ, Mehrotra S. A quantitative increase in regulatory T cells controls development of vitiligo. Journal of Investigative Dermatology. 2014; 134(5):1285-94. (PMCID: PMC3989443). Chatterjee S, Eby JM, Al-Khami AA, Soloshchenko M, Kang HK, Kaur N, Naga OS, Murali A, Nishimura MI, Le Poole IC, Mehrotra S.
Additional publications can be found at: https://www.ncbi.nlm.nih.gov/pubmed/?term=shikhar+mehrotra