Myeloid-derived Suppressor Cells as a Critical Element of Tumor Microenvironment

Myeloid-derived Suppressor Cells as a Critical Element of Tumor Microenvironment

Myeloid-derived Suppressor Cells as a Critical Element of Tumor Microenvironment

Wednesday, November 16, 2011 - 4:00pm

The Wistar Institute, 3601 Spruce St., Philadelphia, PA

Myeloid-derived Suppressor Cells as a Critical Element of Tumor Microenvironment:
Biological Role and Target for Therapeutic Intervention
Dmitry Gabrilovich, M.D., Ph.D.
H. Lee Moffitt Cancer Center & Research Institute

Historically, the main factor limiting the success of cancer immunotherapy was felt to be the inadequate tumor-specific immune responses generated in cancer patients. In recent years, however, advances in the development of novel methods of antigen delivery and the blockade of checkpoint proteins responsible for negative signaling in the immune system as well as the generation of antigen-specific T cells ex vivo with subsequent transfer of these cells to patients after lymphoid depletion, have changed this situation. It is now possible to induce tumor-specific immune responses in most patients treated with various types of cancer immunotherapy.

However, despite these successes, the proportion of patients who benefit clinically from these treatments remains small. Why has our ability to generate tumor-specific immune responses not translated into a clinical benefit?  We investigated a concept that failure of cytotoxic T lymphocytes (CTLs) to eliminate tumor can be independent on inhibition of T-cell function. Inflammation plays an important role in the development and progression of different tumors. In the context of an inflammatory response myeloid cells are the primary recruited effectors. In cancer, these cells are represented by activated macrophages (MΦ), granulocytes, and myeloid-derived suppressor cells (MDSC). Major feature of tumor infiltrating myeloid cells is a production of large amount of peroxynitrite (PNT). In mice, myeloid-derived suppressor cells (MDSCs) were a primary source of PNT. Pre-treatment of tumor cells with PNT or with MDSC inhibited binding of processed peptides to tumor cell associated MHC, and as a result tumor cells became resistant to antigen-specific CTLs. This effect was abrogated in MDSCs with a defect in the production of reactive oxygen species or after treatment with the PNT inhibitor.

As a model of tumor associated inflammation, we used Lewis lung carcinoma (LLC) cells overexpressing IL-1β (to promote myeloid cell accumulation) and ovalbumin (OVA). Adoptive transfer of antigen-specific CTLs after total body irradiation significantly reduced growth of LLC-OVA tumors. In contrast, the therapeutic effect was completely blocked in LLC-OVA-IL-1β tumor-bearing mice. Therapeutic failure was not caused by more profound suppression of T cells in IL-1β expressing tumors. Inhibition of PNT dramatically enhanced the effect of adoptive transfer in different tumor models. 

Our data suggest a novel concept that may contribute to our understanding of the mechanisms of tumor immune escape. The tumor-infiltrating myeloid cells can induce nitration of MHC class I molecules on tumor cells, making them unable to effectively bind and retain peptides and thus rendering the tumor cells resistant to antigen-specific CTLs. This suggests that tumors may escape immune control even if potent CTL responses against the tumor-associated antigens were generated. The escape occurs because tumor cells may not express specific peptides that were used to generate CTLs. It also suggests that this escape can be diminished by blocking the PNT production using pharmacological inhibitors of ROS or RNS.