The other major direction my laboratory has taken includes investigating mechanisms underlying tumor-mediated immunosuppression/tolerance as seen in animals with high tumor burdens. This represents a major obstacle in immune modulated cancer therapy. We have found a significant increase in the number of myeloid suppressor cells (MSC) and T regulatory cells in mice with large tumors. MSC can inhibit T-cell proliferation mediated by anti-CD3 and anti-CD28 (Kusmartsev et al., J. Immunol. 2000), HA peptide- (antigen-specific) mediated proliferation of TCR transgenic T cells, and tumor-specific CTL responses. Interestingly, MSC can be induced to differentiate into mature DCs (Li et al., 2003). Recently, we have established a conditionally-immortalized hematopoietic stem cell system to investigate the development, accumulation, and migration of MSC in tumor-bearing animals. A tumor model with an artificial tumor antigen (HA) has been established and will be utilized to study the underlying mechanisms of immune suppression and tolerance mediated by MSC and T regulatory cells in vivo.
My laboratory is also developing regimens capable of re-activating anergic T cells and identifying immunosuppressive factors secreted by tumor cells or MSC, which may regulate DC development and induce T regulatory cell development in mice and patients with large tumor burdens.
By identifying the molecules involved in immune suppression and tolerance, and studying their underlying mechanisms in hosts with large tumor burdens, we are reassessing a critical avenue to effective and persistent anti-tumor immunity for cancer immune therapies. My ultimate goal is translate the knowledge gained from animal models to comparable studies in clinical trial patients and thus work toward treatments for metastatic diseases. Already, we are expanding collaborations to translate the results of our preclinical research into clinical application for metastatic melanoma, colon, and breast cancers.
