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

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