Cancer Immunology, Inflammation and Tolerance


He Yukai

Yukai He, MD, PhD

Cancer Immunology, Inflammation Program
Professor, Medicine – Gastroenterology and Hepatology
Professor, Graduate Studies
Professor, Biochemistry and Molecular Biology

 

Georgia Cancer Center
1410 Laney Walker Blvd., CN 4150
Phone: 706-721-2728
yhe@augusta.edu

Research Summary

The research in my laboratory is focused on understanding the basic mechanism of immune activation and on translating our findings into developing effective cancer vaccines and immunotherapy for malignant cancers, especially hepatocellular carcinomas.

Research Interests

My laboratory has been focusing our efforts on developing novel effective cancer vaccines and T cell-based cancer immunotherapies using both basic and translational research projects.

Developing novel, effective liver cancer vaccines and immunization

Recently we found that the liver cancer (hepatocellular carcinoma, HCC)-associated self/tumor antigen, alpha fetoprotein (AFP), can be engineered to increase its immunogenicity. Immunization with recombinant lentiviral vectors (lentivectors) expressing such high immunogenic epitope-optimized AFP not only allows us to identify three novel H-2b-restricted epitopes, but more importantly, can effectively reduce the liver tumor nodules induced by carcinogen in mice. To further improve the efficacy of liver cancer vaccines, we are also working with Dr Bjoern Peters of La Jolla Institute for Allergy and Immunology (LIAI) to include CD4 epitopes so that the vaccines can also activate CD4 T cells. For immunization, immune checkpoint blockades have been used to enhance immune responses and to rescue effector function of tumor infiltrating T cells. In addition, my laboratory is working with Dr. Esteban Celis’s laboratory to explore the most effective prime-boost immunization approach to elicit potent and highly responsive memory responses. We are currently working to translate this finding into developing human liver cancer vaccines that can be used to prevent HCC relapse after liver resection and to prevent de novo development of HCC in high-risk populations.

Identifying and cloning high affinity TCR genes that recognize human liver cancer cells for T cell engineering and adoptive cell transfer therapy of HCC

The most effective immunotherapy approach, by far, is adoptive transfer of autologous tumor-specific effector T cells into cancer patients. However, in most cases, it is impossible to isolate and expand sufficient high-quality tumor-specific T cells. One way to circumvent this obstacle is to clone high-affinity TCR genes and use them to engineer autologous T cells to generate sufficient tumor-specific T cells for adoptive transfer. We are using our liver cancer vaccines, different humanized animal models, and human peripheral monocytes to identify and clone high-affinity T cells and their TCR genes that can recognize and kill human HCC tumor cells. The goal is to obtain TCR genes for ex vivo engineering human T cells to achieve HCC immunotherapy.

Designing dendritic cell-targeting virus-like particles as novel liver cancer vaccines

Protein-based vaccines can be used more easily in patients. However, vaccines based on proteins are generally less effective. To create more potent cancer vaccines, we are developing chimeric virus-like particles (VLPs) by equipping them with the capability of targeting and activating dendritic cells. This technology will allow any potential tumor antigen to be able to form VLPs, which will be much more efficiently taken up by antigen presenting cells to initiate tumor-specific immune responses.

Investigating the mechanisms of eliciting highly responsive memory T cells

The major purpose of immunization is to induce highly responsive memory cells that can sense and respond to emerging antigen or tumor cells. However, the mechanism and parameters governing the induction of such highly responsive memory cells are not well understood. We have shown that immunization with lentivector is a very effective approach to elicit high numbers of immune effectors with memory characteristics. We are dissecting the parameters and mechanisms that control the generation of such highly responsive memory T cells after lentivector immunization.

Selected Publications

  1. Liu Z Liu JQ, Shi Y, Zhu X, Liu Z, Li MS, Yu J, Wu LC, He Y, Zhang G, Bai, XF. Epstein-Barr virus-induced gene 3-deficiency leads to impaired anti-tumor T cell responses and accelerated tumor growth. Oncoimmunology.  2015 Jan 9;4(7):e98913
  2. Hong Y, Manoharan I, Suryawanshi A, Shanmugam A, Swafford D, Ahmad S, Chinnadurai R, Manicassamy B, He Y, Mellor AL, Thangaraju M, Munn DH, Manicassamy S. Deletion of LRP5 and LRP6 in dendritic cells enhances anti-tumor immunity Oncoimmunology. 2015 Dec 14;5(4):e1115941. 
  3. Cai J, Fang L, Huang Y, Li R, Xu X, Hu Z, Zhang L, Yang Y, Zhu X, Zhang H, Wu J, Huang Y, Li J, Zeng M, Song E, He Y, Zhang L, Li M. Simultaneous overactivation of Wnt/β-catenin and TGFβ signaling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC. Nat Commun. 2017 Jun 19; 8:15870.  
  4. Wu S ,  Zhu W ,  Peng Y ,  Wang L ,  Hong Y ,  Huang L ,  Dong D ,  Xie J ,  Merchen T ,  Kruse E ,  Guo ZS ,  Bartlett D ,  Fu N , He Y* The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells. Cancer Immunol  Res.  2017, 5(10): 908-12.
  5. Sharma MD, Rodriguez PC, Koehn BH, Baban B, Cui Y, Guo G, Shimoda M, Pacholczyk R, Shi H, Lee EJ, Xu H, Johnson TS, He Y, Mergoub T, Venable C, Bronte V, Wolchok JD, Blazar BR, Munn DH. Activation of p53 in Ly6c+ myeloid precursor cells controls differentiation into immunogenic CD103+ DCs in tumors. Immunity. 2018 Jan 16;48(1):91-106.e6. 
  6. Cai J, Li R, Xu X, Zhang L, Lian R, Fang L, Huang Y, Feng X, Liu X, Li X, Zhu X, Zhang H, Wu J, Zeng M, Song E, He Y, Yin Y, Li J, Li M. CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy.  Nat Cell Biol. 2018 Apr;20 (4):465-478. doi: 10.1038/s41556-018-0065-8. Epub 2018 Mar 28. PubMed PMID: 29593330.
  7. Zhu W ,  Peng Y ,  Wang L ,  Hong Y ,  Jiang X ,  Li Q ,  Liu H ,  Huang L ,  Wu J ,  Celis E ,  Merchen T ,  Kruse E , He Y. Identification of α-fetoprotein-specific T cell receptors for hepatocellular carcinoma immunotherapy. Hepatology. 2018 Aug; 68(2):574-589. doi: 10.1002/hep.29844. Epub 2018 Jun 12.
  8. He YJ, Guo YB, Zhu W, He YK, Hou JL. Immunotherapy: a new era for hepatocellular carcinoma. Hepatoma Res 2018; 4:40. http://dx.doi.org/10.20517/2394-5079.2018.45 .
  9. Wang W, He Y, Wu S. Harnessing the CD8+T-cell subsets with stemness for tumor immunotherapy . Future Oncol. 2018 Aug 24. doi: 10.2217/fon-2018-0238. [Epub ahead of print]. 
  10. Guo ZS, Lu B, Guo Z, Giehl E, Feist M, Dai E, Liu W, Storkus WJ, He Y, Liu Z, Bartlett DL. Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics. J Immunother Cancer. 2019 Jan 9;7(1):6.

Research Team