Honors & Awards

  • Ruth L. Kirschstein Institutional National Research Service Award (T32) Trainee, Cancer-Translational Nanotechnology Training Program, Stanford Medicine (2019-2021)
  • Pilot Grant Awardee, Translational Research and Applied Medicine (TRAM), Stanford Medicine (2020-2021)

Professional Education

  • Doctor of Philosophy, Virginia Polytechnic Institute & State University (2018)
  • Bachelor of Science, George Washington University (2009)
  • Master of Science, Georgetown University (2010)

Lab Affiliations

All Publications

  • Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency. JCI insight Zhang, Y. n., Lee, C. n., Geng, S. n., Li, L. n. 2019; 4 (2)


    Although the importance of the tumor immune environment for the modulation of tumorigenesis and tumor regression is becoming increasingly clear, most of the research related to tumor-immune therapies has focused on adaptive immune cells, while the role and regulation of innate leukocytes such as neutrophils remains controversial and less defined. Here we observed that the selective deletion of Tollip, a key innate immune-cell modulator, led to enhanced tumor immune surveillance in a chemically induced colorectal cancer model. Tollip-deficient neutrophils significantly elevated T cell activation through enhanced expression of the costimulatory molecule CD80, and reduced expression of the inhibitory molecule PD-L1. Mechanistically, Tollip deficiency increased STAT5 and reduced STAT1, the transcription factors responsible for the expression of CD80 and PD-L1, respectively. Through adoptive transfer, we demonstrate that Tollip-deficient neutrophils, but not Tollip-deficient monocytes, are sufficient to drive enhanced tumor immune surveillance and reduced colorectal cancer burden in vivo. Our data reveal a strategy for the reprogramming of neutrophil functions conducive for the enhancement of the antitumor immune environment.

    View details for DOI 10.1172/jci.insight.122939

    View details for PubMedID 30674719

  • Novel reprogramming of neutrophils modulates inflammation resolution during atherosclerosis. Science advances Geng, S. n., Zhang, Y. n., Lee, C. n., Li, L. n. 2019; 5 (2): eaav2309


    Nonresolving inflammation perpetuated by innate leukocytes is involved in the pathogenesis of unstable atherosclerosis. However, the role and regulation of neutrophils related to nonresolving inflammation and atherosclerosis are poorly understood. We report herein that chronic subclinical endotoxemia, a risk factor for atherosclerosis, skewed neutrophils into a nonresolving inflammatory state with elevated levels of inflammatory mediators (Dectin-1, MMP9, and LTB4) and reduced levels of homeostatic mediators (LRRC32, TGFβ, and FPN). The polarization of neutrophils was due to ROS-mediated activation of oxCAMKII, caused by altered peroxisome homeostasis and reduced lysosome fusion. Application of 4-phenylbutyrate (4-PBA) enhanced peroxisome homeostasis of neutrophils, reduced oxCAMKII, and rebalanced the expression profiles of pro- and anti-inflammatory mediators. Adoptive transfer of neutrophils programmed by subclinical endotoxemia rendered exacerbated atherosclerosis. In contrast, transfer of ex vivo programmed neutrophils by 4-PBA reduced the pathogenesis of atherosclerosis. Our data define novel neutrophil dynamics associated with the progression and regression of atherosclerosis.

    View details for DOI 10.1126/sciadv.aav2309

    View details for PubMedID 30775441

    View details for PubMedCentralID PMC6365109

  • Cellular and molecular mechanisms involved in the resolution of innate leukocyte inflammation. Journal of leukocyte biology Rahtes, A. n., Geng, S. n., Lee, C. n., Li, L. n. 2018; 104 (3): 535–41


    Inflammation is a host response to infection or damage and is vital for clearing pathogens and host debris. When this resolution fails to occur, chronic inflammation ensues. Chronic inflammation is typically characterized as a low-grade, persistent inflammatory process that can last for months or even years. This differs from acute inflammation, which is typically a fast, robust response to a stimulus followed by resolution with return to homeostasis. Inflammation resolution occurs through a variety of cellular processes and signaling components that act as "brakes" to keep inflammation in check. In cases of chronic inflammation, these "brakes" are often dysfunctional. Due to its prevalent association with chronic diseases, there is growing interest in characterizing these negative regulators and their cellular effects in innate leukocytes. In this review, we aim to describe key cellular and molecular homeostatic regulators of innate leukocytes, with particular attention to the emerging regulatory processes of autophagy and lysosomal fusion during inflammation resolution.

    View details for DOI 10.1002/JLB.3MA0218-070R

    View details for PubMedID 29688584

    View details for PubMedCentralID PMC6163057

  • Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M. EBioMedicine Rothschild, D. E., Zhang, Y. n., Diao, N. n., Lee, C. K., Chen, K. n., Caswell, C. C., Slade, D. J., Helm, R. F., LeRoith, T. n., Li, L. n., Allen, I. C. 2017; 15: 36–47


    Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m-/- mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m-/- animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m-/- mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m-/- mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.

    View details for DOI 10.1016/j.ebiom.2016.11.039

    View details for PubMedID 27939424

    View details for PubMedCentralID PMC5233813

  • Programming and memory dynamics of innate leukocytes during tissue homeostasis and inflammation. Journal of leukocyte biology Lee, C. n., Geng, S. n., Zhang, Y. n., Rahtes, A. n., Li, L. n. 2017; 102 (3): 719–26


    The field of innate immunity is witnessing a paradigm shift regarding "memory" and "programming" dynamics. Past studies of innate leukocytes characterized them as first responders to danger signals with no memory. However, recent findings suggest that innate leukocytes, such as monocytes and neutrophils, are capable of "memorizing" not only the chemical nature but also the history and dosages of external stimulants. As a consequence, innate leukocytes can be dynamically programmed or reprogrammed into complex inflammatory memory states. Key examples of innate leukocyte memory dynamics include the development of primed and tolerant monocytes when "programmed" with a variety of inflammatory stimulants at varying signal strengths. The development of innate leukocyte memory may have far-reaching translational implications, as programmed innate leukocytes may affect the pathogenesis of both acute and chronic inflammatory diseases. This review intends to critically discuss some of the recent studies that address this emerging concept and its implication in the pathogenesis of inflammatory diseases.

    View details for DOI 10.1189/jlb.6MR0117-027RR

    View details for PubMedID 28476750

    View details for PubMedCentralID PMC5557635

  • Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic colitis. Scientific reports Diao, N. n., Zhang, Y. n., Chen, K. n., Yuan, R. n., Lee, C. n., Geng, S. n., Kowalski, E. n., Guo, W. n., Xiong, H. n., Li, M. n., Li, L. n. 2016; 6: 34672


    Functionally compromised neutrophils contribute to adverse clinical outcomes in patients with severe inflammation and injury such as colitis and sepsis. However, the ontogeny of dysfunctional neutrophil during septic colitis remain poorly understood. We report that the dysfunctional neutrophil may be derived by the suppression of Toll-interacting-protein (Tollip). We observed that Tollip deficient neutrophils had compromised migratory capacity toward bacterial product fMLF due to reduced activity of AKT and reduction of FPR2, reduced potential to generate bacterial-killing neutrophil extra-cellular trap (NET), and compromised bacterial killing activity. On the other hand, Tollip deficient neutrophils had elevated levels of CCR5, responsible for their homing to sterile inflamed tissues. The inflamed and incompetent neutrophil phenotype was also observed in vivo in Tollip deficient mice subjected to DSS-induced colitis. We observed that TUDCA, a compound capable of restoring Tollip cellular function, can potently alleviate the severity of DSS-induced colitis. In humans, we observed significantly reduced Tollip levels in peripheral blood collected from human colitis patients as compared to blood samples from healthy donors. Collectively, our data reveal a novel mechanism in Tollip alteration that underlies the inflamed and incompetent polarization of neutrophils leading to severe outcomes of colitis.

    View details for DOI 10.1038/srep34672

    View details for PubMedID 27703259

    View details for PubMedCentralID PMC5050405

  • Detection of differential fetal and adult expression of chloride intracellular channel 4 (CLIC4) protein by analysis of a green fluorescent protein knock-in mouse line. BMC developmental biology Padmakumar, V. n., Masiuk, K. E., Luger, D. n., Lee, C. n., Coppola, V. n., Tessarollo, L. n., Hoover, S. B., Karavanova, I. n., Buonanno, A. n., Simpson, R. M., Yuspa, S. H. 2014; 14: 24


    Chloride Intracellular Channel 4 (CLIC4) is one of seven members in the closely related CLIC protein family. CLIC4 is involved in multiple cellular processes including apoptosis, cellular differentiation, inflammation and endothelial tubulogenesis. Despite over a decade of research, no comprehensive in situ expression analysis of CLIC4 in a living organism has been reported. In order to fulfill this goal, we generated a knock-in mouse to express Green Fluorescent Protein (GFP) from the CLIC4 locus, thus substituting the GFP coding region for CLIC4. We used GFP protein expression to eliminate cross reaction with other CLIC family members.We analyzed CLIC4 expression during embryonic development and adult organs. During mid and late gestation, CLIC4 expression is modulated particularly in fetal brain, heart, thymus, liver and kidney as well as in developing brown adipose tissue and stratifying epidermis. In the adult mouse, CLIC4 is highly expressed globally in vascular endothelial cells as well as in liver, lung alveolar septae, pancreatic acini, spermatogonia, renal proximal tubules, cardiomyocytes and thymic epithelial cells. Neural expression included axonal tracks, olfactory bulb, Purkinje cell layer and dentate gyrus. Renal CLIC4 expression was most pronounced in proximal tubules, although altered renal function was not detected in the absence of CLIC4. Myeloid cells and B cells of the spleen are rich in CLIC4 expression as are CD4 and CD8 positive T cells.In a comprehensive study detailing CLIC4 expression in situ in a mouse model that excludes cross reaction with other family members, we were able to document previously unreported expression for CLIC4 in developing fetus, particularly the brain. In addition, compartmentalized expression of CLIC4 in specific adult tissues and cells provides a focus to explore potential functions of this protein not addressed previously.

    View details for DOI 10.1186/1471-213X-14-24

    View details for PubMedID 24886590

    View details for PubMedCentralID PMC4073518

  • Dipeptidyl peptidases as survival factors in Ewing sarcoma family of tumors: implications for tumor biology and therapy. The Journal of biological chemistry Lu, C. n., Tilan, J. U., Everhart, L. n., Czarnecka, M. n., Soldin, S. J., Mendu, D. R., Jeha, D. n., Hanafy, J. n., Lee, C. K., Sun, J. n., Izycka-Swieszewska, E. n., Toretsky, J. A., Kitlinska, J. n. 2011; 286 (31): 27494–505


    Ewing sarcoma family of tumors (ESFT) is a group of aggressive pediatric malignancies driven by the EWS-FLI1 fusion protein, an aberrant transcription factor up-regulating specific target genes, such as neuropeptide Y (NPY) and its Y1 and Y5 receptors (Y5Rs). Previously, we have shown that both exogenous NPY and endogenous NPY stimulate ESFT cell death via its Y1 and Y5Rs. Here, we demonstrate that this effect is prevented by dipeptidyl peptidases (DPPs), which cleave NPY to its shorter form, NPY(3-36), not active at Y1Rs. We have shown that NPY-induced cell death can be abolished by overexpression of DPPs and enhanced by their down-regulation. Both NPY treatment and DPP blockade activated the same cell death pathway mediated by poly(ADP-ribose) polymerase (PARP-1) and apoptosis-inducing factor (AIF). Moreover, the decrease in cell survival induced by DPP inhibition was blocked by Y1 and Y5R antagonists, confirming its dependence on endogenous NPY. Interestingly, similar levels of NPY-driven cell death were achieved by blocking membrane DPPIV and cytosolic DPP8 and DPP9. Thus, this is the first evidence of these intracellular DPPs cleaving releasable peptides, such as NPY, in live cells. In contrast, another membrane DPP, fibroblast activation protein (FAP), did not affect NPY actions. In conclusion, DPPs act as survival factors for ESFT cells and protect them from cell death induced by endogenous NPY. This is the first demonstration that intracellular DPPs are involved in regulation of ESFT growth and may become potential therapeutic targets for these tumors.

    View details for DOI 10.1074/jbc.M111.224089

    View details for PubMedID 21680731

    View details for PubMedCentralID PMC3149342