Issue No. 20, September 2018
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, M.Ph., Ph.D., the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by the VIMM members.     
Gr1 −/low CD11b −/low MHCII+ Myeloid Cells Boost T Cell Anti-Tumor Efficacy
 
  • Antigen presenting cells (APCs) take up tumor antigens and present them to T cells for the induction of anti-tumor immune responses.
  • Conventional APCs that express MHC class II (MHCII) and co-stimulatory molecules include dendritic cells (DCs) and macrophages. Atypical APCs include mast cells, basophils, and eosinophils.
  • The Manjili laboratory recently identified a unique type of APCs, Gr1−/lowCD11b−/low cells with a granularity and size characteristic of myeloid cells and with the ability to process antigen for cross presentation. An increased frequency of Gr1−/lowCD11b−/low APCs was associated with increased survival of animals with a metastatic mammary carcinoma.
  • Interestingly, human CD33+CD11b−/lowHLADR+ myeloid cells appear to have immune stimulatory function similar to murine Gr1−/lowCD11b−/lowMHCII APCs, boosting anti-tumor immune responses.
 
Antigen Presenting Cells as Cancer Vaccines

Dendritic cells (DCs) play a central role in antigen cross-presentation for the induction of the immune response against infectious diseases and cancer. However, their efficacy as a cell-based vaccine is limited because of host-derived immune suppressive cells such as myeloid-derived suppressor cells (MDSCs). The accumulation of MDSCs hinders protective immune responses to cancer and infectious diseases.
 
Sipuleucel-T is the only FDA-approved therapeutic vaccine for metastatic prostate cancer. The vaccine uses readily isolated circulating DCs cultured with prostate tumor antigen and GM-CSF. However, circulating DCs are very rare and tumor-induced immune suppressive cells, such as MDSCs, limit their efficacy in inducing a sustained anti-tumor immune response. Therefore, there is an urgent need to identify a new class of APCs that is highly efficient in orchestrating profound anti-tumor immunity to facilitate the development of cell-based cancer vaccines.
 
The Manjili laboratory recently identified a unique class of APCs that do not express pan markers of myeloid DCs (CD11c), plasmacytoid DCs (Ly6C) or macrophages (F4/80). They are characterized as Gr1 /low CD11b /low MHCII APCs (1). These APCs appear to interact with B cells (see Figure below), a phenomenon that has classically been described to occur between DCs and B cells. Gr1 /low CD11b /low MHCII APCs are unique in the following ways: (i) they are more abundant than DCs, and are associated with B cells, (ii) they are heterogeneous in the expression of Ly6G and Ly6C, making them highly effective in simultaneous antigen uptake and antigen presentation, (iii) they retain their immune stimulatory function during tumor burden, (iv) their frequency is inversely correlated with MDSCs, and (v) they can boost anti-tumor immune responses despite the presence of MDSCs (2). These novel APCs may prove useful as a cancer vaccine in the future.
Figure legend:

GR1 -/low CD11b -/low MHCII cells contain myeloid cells and B cells. Hundred images/events from the CD3-CD20- and CD20+ populations were analyzed for doublets by inspecting each image manually. Also, doublets within CD20+ cells were analyzed based on morphology showing B cell:B cell (B:B) or B cell:Myeloid cell (B:Myel) interactions. 
Funding : This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087, the American Association of Immunologists’ Careers in Immunology Fellowship, and pilot funding from the VCU Massey Cancer Center supported, in part, with funding from NIH/NCI Cancer Center Support Grant P30 CA016059. Services and products in support of the research project were generated by the VCU Massey Cancer Center Flow Cytometry Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.
Publications:
 
2. Payne KK , Zoon CK , Wan W , Marlar K , Keim RC , Kenari MN , Kazim AL , Bear HD , Manjili MH . Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. Breast Cancer Res Treat. 2013 Nov;142(1):45-57. PMCID: PMC4844228
 
About the Investigators: Masoud H. Manjili, PhD, DVM is Associate Professor of Microbiology and Immunology, and Affiliate Associate Professor of Pathology in the Virginia Commonwealth University (VCU) School of Medicine, and is a Full Member of the VCU Institute of Molecular Medicine (VIMM). Xiang-Yang Wang, PhD, is Professor of Human and Molecular Genetics (HMG), Associate Scientific Director of Immunology of the VCU Institute of Molecular Medicine (VIMM) and Mary Anderson Harrison Distinguished Professor in Cancer Research in the VCU Massey Cancer Center (MCC), VCU School of Medicine, Richmond, VA. Harry D. Bear, MD, PhD is Walter Lawrence, Jr. Distinguished Professor of Oncology; Division Chair Surgical Oncology, Department of Surgery; Professor, Departments of Surgery, Microbiology & Immunology, VCU School of Medicine; Director, Breast Health Center, VCU Massey Cancer Center; Medical Director, Massey Cancer Center Clinical Trials Office.