Todd A. Fehniger, M.D., Ph.D.

Associate Professor
Internal Medicine

Immunology Program

  • 314-747-1385

  • 314-747-1547

  • 314-362-9832 (Administrator: Denise Zurliene)

  • 314-362-9333

  • Southwest Tower, Room 638



  • cancer, cytokine, immunology, innate immunity, NK cells, small noncoding RNAs, immunotherapy, lymphoma, genomics

  • My laboratory is focused on the molecular mechanisms regulating natural killer cell activation, novel methods to use NK cells as immunotherapy for cancer, and lymphoma genomics.

Research Abstract:

1. microRNA regulation of NK cell development and function

NK cells are innate immune lymphocytes that are important for host defense against infections and malignant transformation. NK cells require numerous cytokine signals for development, homeostasis, and activation. We and others have demonstrated that mature `resting` NK cells in peripheral lymphoid tissues require cytokine activation to `arm` (or `prime`) them for efficient effector functions such as cytotoxicity or cytokine production. Interestingly, multiple NK cell effector molecules appear regulated in resting NK cells at the post-transcriptional level, including perforin, granzyme B, and interferon gamma. This suggests that resting NK cells may store messenger RNAs and block their translation as a general strategy to be poised to respond once recognizing the appropriate target cell or entering a cytokine-rich inflamed environment. What is the molecular mechanism used by NK cells to mediate such a translational blockade? We are pursuing this question specifically by evaluating how two cytotoxic effector molecule mRNAs (granzyme B and perforin) are controlled in resting NK cells, and more generally by using unbiased discovery approaches (transcriptional profiling, proteomics) to define the NK cell activation program at the molecular level and identify regulatory players, currently focusing on microRNAs.

MicroRNAs are a large family of small RNAs that primarily bind to the 3`UTR of mRNAs and block protein production. We are currently defining microRNA expression in human and mouse NK cells, and evaluating the individual roles of specific microRNAs or microRNA clusters on NK cell biology.

2. Cytokine-activation to enable human NK cell function

We also study approaches to enhance the functional status of NK cells, and currently focus on cytokines or cytokine combinations. Human NK cells exhibit a prolonged enhanced functional state after combined cytokine-activation with IL-12, IL-15, and IL-18, and we are currently exploring the functional biology of these cytokine pre-activated cells in collaboration with Megan Cooper`s laboratory, as well as translating this approach as a novel immunotherapy strategy for cancer.

3. Lymphoma Genomics

Lymphoma is a common malignancy that affects tens of thousands of patients each year. Currently, we are collaborating with The Genome Institute to investigate the somatic mutations present in follicular lymphoma, and how these mutations may affect lymphoma progression, transformation, and correlate with clinical outcomes.

Selected Publications:

Sullivan RP, Leong JW, Fehniger TA. MicroRNA regulation of natural killer cells. Front Immunol. 4(44)L doi: 10.3389/fimmu.2013.00044. Epub Feb 28, 2013. [Review] PMID: 23450173

Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, Cooper MA, Fehniger TA. Cytokine activation induced human memory-like NK cells. Blood [Sep 14 2012 Epub] 120:4751-60, 2012 PMID: 22983442

Sullivan RP, Leong JW, Schneider SE, Keppel CR, Germino E, French AR, Fehniger TA. MicroRNA deficient NK cells exhibit decreased survival but enhanced function. J Immunol, [Feb 29 Epub ahead of print] 188:3019-30, 2012. PMID: 22379033

Fehniger TA, Wylie T, Germino E, Leong JW, Magrini VJ, Koul S, Keppel CR, Schneider SE, Koboldt DC, Sullivan RP, Heinz ME, Crosby SD, Nagarajan R, Ramsingh G, Link DC, Ley TJ, Mardis ER. Next-generation sequencing identifies the natural killer cell microRNA transcriptome. Genome Research, Epub 2010 Oct 8. 20(11):1590-605, 2010. PMID: 20935160

White DW, Keppel CR, Schneider SE, Reese TA, Coder J, Payton JE, Ley TJ, Virgin HW, Fehniger TA. Latent herpesvirus infection arms NK cells. Blood 115:4377-4383, 2010. [Feb 4 Epub, 2010] PMID: 20139098

Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR, Ley TJ. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 2007 26(6):798-81.

Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 2003 101(8):3052-7.

Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 2001 193(2):219-31.

Last Updated: 8/14/2013 10:13:52 AM

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