by Jalwa Afroz

Metastasis is the spreading of cancer cells beyond their site of origin and evading immune responses. Specifically, metastasis is the leading cause of cancer deaths (over 90%). It is easier for circulating tumor cells to localize to the lung because of the vast capillary networks that provide constant blood flow to the lungs. In addition, metastasis formation of the primary traveling tumor cells must evade the immune responses at the site of its secondary colonization. However, researchers hypothesized that immunoregulatory mechanisms favor tumor colonization.

T-cells coordinate immune response and effector T-cells activate the immune response to support the elimination of infections and cancer. On the other hand, regulatory T-cells suppress effector T-cell function in order to prevent allergic reactions and large autoimmune responses. This could pose a problem since effector T-cell responses are suppressed even to continuous innocuous foreign antigens. Particularly, the oxygen-sensitive prolyl hydroxylase domain (PHD) enzymes catalyze post-translational hydroxylation of HIF, which drive effector T cell responses or IFN- production within regulatory T cells. When a tumor colonizes, PHD proteins promote regulatory T-cell growth but restrain IFN-, which is a key regulator in clearing cancers.

Dr. David Clever and his team showed that PHD expression in T-cells suppresses pulmonary inflammation against foreign antigens and promotes tumor colonization of the lung. They had injected cancerous melanoma cells into knockout mice lacking the PHD protein in their T-cell and wild-type mice with functioning PHD proteins. The results demonstrated that the wild-type mice showed large amounts of cancerous cells in the lungs, and the knockout mice showed no evidence of melanoma in the lungs. Thus, the inhibition of PHD proteins or deletion of T-cell-intrinsic response, that promotes PHD protein activation, limits tumor colonization in the lungs and improves the effectiveness of T-cell-based cell therapy. The application of these findings to immunotherapy clinical trials is still being investigated.

References:

1. Clever, et al., Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell (2016). doi: 10.1016/j.cell.2016.07.032.
2. Image retrieved from: http://vector.childrenshospital.org/2014/08/curbing-metastasis-in-lung-cancer-by-taking-a-cue-from-the-nervous-system-2/