Tumor-bearing animals and cancer patients exhibit defects in myelopoiesis, resulting in the accumulation of immature myeloid cells (ImC). ImC have shown to induce a profound state of immune suppression by interfering with the function of tumor-specific T cells through several mechanisms, including the production of reactive oxygen species, or increased arginine activity. Thus, there is increased interest in developing strategies that allow the elimination of ImC in cancer immunotherapy protocols. In this study we sought to develop accurate and reliable methods for the isolation of ImC in the peripheral blood of RCC patients and functionally validate their immunosuppressive action in vitro. In order to reverse ImC-mediated immunosuppressive activity, we used various differentiation agents, including all-trans retinoic acid to differentiate ImC to a mature, non-suppressive phenotype. We show that patients with advanced RCC possess significantly elevated levels of ImC in their peripheral circulation, and that ImC can be isolated from PBMC for further phenotypic and functional characterization. Moreover, we demonstrated that ImC isolated from RCC patients dramatically suppress antigen-specific T-cell responses in vitro, and that ImC-mediated immunosuppression can be abrogated in a dose dependent fashion by incubation with the differentiation agent ATRA. Our data suggest that ATRA-mediated ImC differentiation may represent a clinically applicable strategy capable of reversing tumor-mediated immunosuppression and enhancing the therapeutic efficacy of cancer vaccines. A pilot study exploring this novel concept is currently ongoing at our institution.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]