Radical Nitrogen Species Shield Tumors from Immune System Attack

Cancer researchers have found a molecular mechanism that protects tumors by preventing cytotoxic T lymphocytes (CTLs) from reaching the core of the tumor.

Investigators at Venetian Oncological Institute (Padua, Italy) and colleagues from several other Italian research institutions were investigating how tumors protect themselves from immune system attack. In particular, they focused on the role of the reactive nitrogen species (RNS) produced inside the tumor.

RNS are produced in animals starting with the reaction of nitric oxide with superoxide to form peroxynitrite. Superoxide anion is a reactive oxygen species that reacts quickly with nitric oxide (NO) in the vasculature. The reaction produces peroxynitrite and depletes the bioactivity of NO. This is important because NO is a key mediator in many important vascular functions including regulation of smooth muscle tone and blood pressure, platelet activation, and vascular cell signaling.

Peroxynitrite itself is a highly reactive species, which can directly react with various biological targets and components of the cell including lipids, thiols, amino acid residues, DNA bases, and low-molecular weight antioxidants. However, these reactions happen at a relatively slow rate. This slow reaction rate allows it to react more selectively throughout the cell. Peroxynitrite is able to get across cell membranes to some extent through anion channels. Additionally peroxynitrite can react with other molecules to form additional types of RNS including nitrogen dioxide and dinitrogen trioxide as well as other types of chemically reactive free radicals.

The investigators described in the September 19, 2011, online edition of the Journal of Experimental Medicine a novel RNS-dependent posttranslational modification of cytokines that had a profound impact on T-cell recruitment to mouse and human tumors. The modification came about from the reaction between RNS and the cytokine CCL2 (chemokine (C-C motif) ligand 2). CCL2 is a small cytokine belonging to the CC chemokine family that is also known as monocyte chemotactic protein-1 (MCP-1) and small inducible cytokine A2. CCL2 recruits monocytes, memory T cells, and dendritic cells to sites of tissue injury, infection, and inflammation.

Nitration of CCL2 by RNS at the tumor core destroyed its ability to attract T-cells, which resulted in CTLs being trapped in the stroma that surrounds cancer cells where active CCL2 persists.

The study concludes with the finding that preconditioning of the tumor microenvironment with novel drugs that inhibited CCL2 modification facilitated CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy.

Related Links:
Venetian Oncological Institute