Stem Cell Immunobiology
Cancer Stem Cells
The cancer stem cell (CSC) hypothesis posits that tumors contain rare subpopulations of cells with increased tumorigenic potential able to initiate tumors in serial xenograft assays. These cells generate differentiated non-tumorigenic progeny that comprise the bulk of the tumor mass, while simultaneously maintaining the seed cancer stem cell population. The CSC hypothesis may explain the long-term recurrence of many tumors in the face of conventional anti-neoplastic therapies, such as radiation and chemotherapy. These treatments target rapidly dividing cells, effectively destroying differentiated tumor cells; however, they leave the slowly-proliferating cancer stem cell intact, which can then reconstitute the tumor, resulting in cancer relapses.
Thus, therapeutic modalities which specifically target the cancer stem cell would be an improvement over current, non-specific, cytotoxic treatments because they would deprive the tumor of its self-renewing capacity, thus preventing relapses and, in combination with current therapies, would perhaps lead to tumor stasis and eventual involution. One such strategy would be immunologic, using primed lymphocytes to recognize targets unique to, or specifically upregulated in, CSC.
Toward this end, the Zanetti lab investigates the specific immunologic characteristics of stem cells in general, and CSC, in particular. Little is known concerning the antigen processing and presentation machinery in stem cells, let alone peptide-HLA (human leukocyte antigen) complexes unique to stem cells that may serve as an immunologic target. A relevant target on CSC may be telomerase, a ribonucleoprotein complex that preserves the ends of chromosomes during replication, thus ensuring genomic integrity during cell division. Its gradual loss is implicated in cell senescence and differentiation, and its maintenance is crucial to the continued self-renewal of stem and progenitor cells. This lab was one of the first in the world to immunologically target telomerase peptide presentation on cancer cells via vaccination, and continues to try and establish telomerase as a target on CSC. The lab uses cellular and molecular immunological approaches to study human CSC antigen presentation and seeks collaborators with validated human CSC model systems.
Human Pluripotent Stem Cells
Our investigation of stem cell antigen presentation is not limited to cancer. Human pluripotent stem cells (hPS) have great therapeutic promise because of their potential to differentiate into any cell type in the body. These cells fall into two major categories: embryonic stem (hES) cells, which are derived from embryos, and induced pluripotent stem (iPS) cells, which are generated from adult cells. Both of these cell types have been proposed as a source for cell-based therapy for various diseases including Parkinson’s disease, Type I Diabetes, muscular dystrophy, and heart disease.
However, while much work has been done in elucidating the pathways of differentiation, less consideration has been given to how the immune system would react to transplanted hPS cells and their differentiated derivatives, and how to circumvent possible barriers to transplantation. The Zanetti lab is interested in the interface of stem cell biology and immunology and studies the immunobiology of stem cells in anticipation of their eventual therapeutic realization. Initial studies have taken place characterizing antigen presentation machinery in stem cells of different origins including brain. Future studies aim at characterizing antigen presentation during reprogramming and stem cell differentiation, as well as the ability of these cells to evoke a robust immune response.