12:00 AM
 | 
Oct 23, 2008
 |  BC Innovations  |  Cover Story

Suppressing the Suppressors

Last week's termination of Cell Genesys Inc.'s Phase III trial of GVAX for prostate cancer is the latest in a long line of failures for cancer vaccine developers. A variety of molecular and cellular mechanisms have contributed to the disappointing outcomes, but a key driver remains the ability of the tumor microenvironment to suppress the host antitumor response.

New research now has identified a signaling pathway that is activated in immunosuppressive myeloid cells within the microenvironment, raising the possibility that this pathway could be targeted to overcome immunosuppression and boost cancer vaccine efficacy.

Two papers published in The Journal of Experimental Medicine 1 and The Journal of Immunology 2 build on previous work describing the role of myeloid-derived suppressor (MDS) cells in tumor progression.3,4 MDS cells derive from hematopoietic precursor cells. They are recruited to tumors from the blood and bone marrow in response to tumor-secreted factors like IL-6.

MDS cells can induce host T cell tolerance,5,6 which in turn can prevent cancer immunotherapy from eliciting a robust antitumor response.

"Together with regulatory T cells, MDS cells are likely one of the most important mechanisms used by tumors to suppress immune activity in the tumor microenvironment," said Paulo Maciag, senior scientist at cancer immunotherapy developer Advaxis Inc.

Until now, the signaling pathways underlying the production and accumulation of MDS cells within the tumor microenvironment were unclear. The new papers describe the role played by two members of the S100 family of calcium-binding proteins-S100A8 (MRP8; calgranulin A)

and S100A9 (MRP14; calgranulin B)-in the maintenance of immunosuppressive MDS cells at the tumor site (see "Blocking immunosuppression in the tumor microenvironment").

In the JEM paper, researchers at the H. Lee Moffitt Cancer Center and colleagues reported that production of MDS cells in tumor-bearing mice requires upregulation of S100A9.

In mice injected with lymphoma cells, knockout of S100A9 resulted in greater tumor infiltration of CD8 and CD4 T cells and less accumulation of MDS cells than that seen in wild-type mice. The knockout mice had higher rates of tumor rejection and lower tumor size than their wild-type littermates.

In the Journal of Immunology paper, a team at the University of Maryland, Baltimore County and the Burnham Institute for Medical Research reported that MDS cells synthesize and secrete S100A8 and S100A9 heterodimers that bind glycoprotein receptors on the surface of other MDS cells. This promotes accumulation of the immunosuppressive cells in the blood and lymphoid organs of tumor-bearing mice.

In mice with metastatic disease, an antibody targeting glycoprotein receptors lowered serum levels of MDS cells, S100A8 and S100A9 compared with those seen in mice that received a control antibody.

The authors of the Journal of Immunology article concluded that targeting the S100A8 and S100A9 heterodimer "may improve immunotherapy with cancer vaccines and other immune strategies that require an immune-competent host."

"Any cancer vaccine that relies on activation of CD4 and CD8 T cells will presumably benefit from prior neutralization of immunosuppressive MDS cells, and targeting the S100 proteins could help achieve this," noted Suzanne Ostrand-Rosenberg, corresponding author on the paper and chair of...

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