Cancer Immunobiology Laboratory

Hong-Ming Hu, Ph.D.

Hong-Ming Hu, Ph.D.

The long-term goal of the Laboratory of Cancer Immunobiology, led by Hong-Ming Hu, Ph.D., is to understand how the immune system senses tumor cells and develop effective cancer vaccines and immunotherapy strategies. The therapeutic cancer vaccine requires activation and expansion of therapeutic effector T cells in vivo to levels above the threshold required for tumor eradication and prevention of recurrence in tumor-bearing hosts. For most bacterial and viral infections, the robust innate and adaptive immune responses generally result in control of infection and development of a strong memory response. In contrast, for patients with cancer, the host immune system often fails to control the growth of cancer despite the fact that tumor cells replicate at a much slower rate than bacteria and viruses.

The major differences between the immunology of infection and tumors include the following: tumor cells lack strong antigens and, as compared to infections, tumor cells are sensed differently by innate immune system, which orchestrates the subsequent adaptive immune response. The Laboratory of Cancer Immunobiology investigates how tumor cells, live or dead, are sensed by innate immunity and how tumor antigens are cross-presented by host professional antigen presenting cells. Better understanding the mechanisms of early stage of immune recognition of tumor cells would lead to design novel cancer vaccines and immunotherapy strategies.

Current Projects

Tumor cells contain a large array of short-lived proteins that are ignored by a host immune system because they are rapidly degraded and disposed, thus they could not be cross-presented by host dendritic cells and are ignored by the host immune system. Our hypothesis is that these short-lived proteins could elicit strong tumor-specific immune responses when they are cross-presented by mature dendritic cells in a sufficient quantity if their degradation could be prevented. Preliminary studies in our laboratory have discovered that tumor cells are actively blebbing (Zeiosis) when they are treated with proteasome inhibitors. We refer to these zeiotic blebs as "DRibbles" because they contain ubiquitinated proteins possibly derived from defective ribosomal products (DRiPs) or other short-lived proteins (DRiPs in Blebs).  DRibbles have induced a strong tumor-specific T-cell immunity and mediated tumor regression in several tumor models. Currently, we are working to determine the underlining mechanisms that enable DRibbles to induce a strong therapeutic T-cell mediated antitumor immunity in tumor-bearing mice as a preliminary step in developing immune-based therapies for human cancers.

Recently we demonstrated that autophagosomes are a major component of DRibbles and macroautophagy of tumor cells is critical for efficient cross-presentation of tumor-associated antigens.

Based on our findings and published literature from other scientists, we hypothesized that autophagic cell death tumor cells represents an immunogenic death pathway to increase antitumor immune responses. Consistent with this hypothesis, we recently found that autophagosomes express ligands for pattern recognition receptor, CLEC9A, whose expression is restricted to a subset of dendritic cells specialized in cross-presentation of cell-associated antigens. The CLEC9A expressing subset of dendritic cells is key population in both human and mice, which plays a dominant role in the T-cell activation in lymph nodes. Our lab is investigating this novel subset of dendritic cells in both human and murine systems. In addition, we began to reveal that tumor-derived autophagosomes are recognized by the innate immune system via multiple pathways including CLEC9A, TLRs, and other intracellular receptors that activate inflammasome and production of inflammatory cytokines. We began to delineate the regulatory role of these different pathways in the tumor growth and development of immune responses against tumor cells particularly in tumor microenvironment.

We also found that DRibbles can induce T-cell mediated immune responses against tumor-associated antigens shared by multiple tumors but not normal tissues in both human and mice. In collaboration with Amy Moran, Ph.D. in the Laboratory of Basic Immunology, we are working toward to identify these shared tumor antigens and T-cell receptors (TCRs) that recognize these antigens using new transgenic mice developed by Dr. Moran. These TCRs could potentially be used for the adoptive T cell therapy approach for cancer treatment. Tumor-specific antigens shared by multiple tumor types will be excellent vaccine candidates for active immunotherapy approaches.

In collaboration with Jun Jiao, Ph.D., of Portland State University, we are developing new nanomaterials that could deliver agents into tumors to induce autophagic cell death and immune adjuvants.

Current Research Collaborations

Melanoma - Exploiting Lymphopenia to Augment the Adoptive Immunotherapy of Melanoma Patients 

Clinical:

  • Walter J. Urba, M.D., Ph.D., director cancer research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute

Adoptive Cellular Therapy in Melanoma

Clinical:

  • Walter J. Urba, M.D., Ph.D., director cancer research. Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
  • Brendan Curti, M.D., director of genitourinary cancer research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute

NSCLC - Clinical Trial of Dribble Vaccine in NSCLC

Clinical:

  • Walter J. Urba, M.D., Ph.D., director cancer research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute

Lab:

  • Bernard A. Fox, Ph.D., Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute

Full List of Publications 

Laboratory Team

Hong-Ming Hu, Ph.D.
Zhi Hua Cui
Yongbin Mou, Ph.D., M.D., DDS
Yun Xing, Ph.D. student
Guangjie Yu, Ph.D. student
Hongyan Ren, Ph.D. student

Laboratory Alumni

Rui Li, M.D., Ph.D.
Yiwei Chu, M.D.
Min Fang, Ph.D.
Peter Hao, M.D.
Marka Crittenden, M.D., Ph.D.
Erik LeShane, Ph.D.
Yuhuan Li, Ph.D.
Ashling O'hara, M.S.
Puiyi Pang, M.S.
Shu Su, M.D., Ph.D.
Lixin Wang, Ph.D.
Guojun Yang, M.D.