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
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.
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.
*He Y, Zhang J, Mi Z, Robbins P, Falo, LD, Jr. (2005) Immunization with lentiviral vector-transduced dendritic cells induces strong and long-lasting T cell responses and therapeutic immunity. J Immunol. 174:3808-17.
*He Y, Zhang J, Donahue C, Falo, LD, Jr. (2006) Skin-Derived Dendritic Cells Induce Potent CD8+ T Cell Immunity in Recombinant Lentivector-Mediated Genetic Immunization. Immunity.24:643-56.
He Y, Falo LD. (2007) Lentivirus as a potent and mechanistically distinct vector for genetic immunization. Current Opinion in Molecular Therapeutics. 9 (5):439-46.
*He Y, Munn D, Falo, LD. (2007) Recombinant lentivector as a genetic immunization vehicle for antitumor immunity. Expert Review in Vaccines.6(6):913-24.
Liu Y, Peng Y, Mi M, Guevara-Patino J, Munn DH, Fu N, He Y*. (2009) Lentivector immunization stimulates potent CD8 T cell responses against melanoma self-antigen tyrosinase related protein 1 and generates antitumor immunity in mice. J Immunol.182:5960-9.
Zhou Q, Xiao H,Liu Y, Peng Y, Chandler P, Munn DH, Mellor A, Fu N, He Y*. (2010) Blockade of PD1 signaling pathway rescues the effector function of tumor infiltrating T cells and improves the antitumor efficacy of lentivector immunization. J. Immunol. 185: 5082-92.
Hong Y, Peng Y, Mi M, Munn DH, Wang GQ, He Y*. (2011) Lentivector expressing HBsAg and immunoglobulin Fc fusion antigen induces potent immune responses and results in seroconversion in HBsAg transgenic mice. Vaccine. 29(22):3909-16.
Xiao H, Peng Y, Hong Y, Liu Y, Guo ZS, Bartlett DL, Fu N, He Y*. (2011) Lentivector prime and vaccinia virus vector boost generate high quality CD8 memory T cells and prevent autochthonous mouse melanoma. J Immunol. 187(4):1788-96.
Hong Y, Peng Y, Xiao H, Mi M, Munn D, He Y*. (2012) Activation of endogenous CD4 T cells stimulates favorable immunological changes in the tumor milieu and enhances antitumor effect of lentivector immunization. J Immunol. 188(10):4819-27.
Xiao H, Peng Y, Hong Y, Huang L, Guo ZS, Bartlett DL, Fu N, Munn DH, Mellor A, He Y*. (2013) Local administration of TLR ligands rescues the function of tumor-infiltrating CD8-T cells and enhances the antitumor effect of lentivector immunization. J Immunol.190: 5866–73.
Hong Y, Peng Y, Guo ZS, Guevara-Patino J, Pang J, Butterfield LH, Mivechi NF, Munn DH, Bartlett DL, *He Y. (2014) Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology 59(4):1448-58.
*He Y, Hong Y, Mizejewski GJ. (2014) Engineering Alpha-fetoprotein-based gene vaccines to prevent and treat hepatocellular carcinoma: Review and Future Prospects. Immunotherapy. 6(6):725-36.
Sha Wu, Wei Zhu, Yibing Peng, Lan Wang, Yuan Hong, Lei Huang, Dayong Dong, Junping Xie, Todd Merchen, Edward Kruse, Zong Sheng Guo, David Bartlett, Ning Fu, and Yukai He. The antitumor effects of vaccine-activated CD8 T cells associate with weak TCR signaling and induction of stem-like memory T cells. (2017 In revision)