International Business Department           Liu Bojia           March 04, 2023

  In our understanding, cancer cells proliferate very rapidly and they can build microenvironments that suppress the immune system, which favours tumour survival and further growth. However, in the early stages, the mutated cells that arise by chance are not able to do whatever they want as we think, and the immune system promptly removes these cells that are harmful to the organism.

  However, under close immune system surveillance, there are still a very few that slip through the net, and they lay the groundwork for tumour development. Scientists have long wondered what means are used by these cancer cells that initially escape monitoring. If the secrets are understood, perhaps we can hopefully stop cancer at its source.

  According to a recent paper published in Nature, scientists at the Massachusetts Institute of Technology (MIT), in collaboration with the Dana-Farber Cancer Institute, have discovered that a protein called SOX17 helps cancer cells to "go invisible", and that colon cancer cells that turn on theSOX17geneearly on in their lifecan survive without being monitored by the immune system. The reason for the study's focus on colon cancer cells.

  The study focuses on colon cancer cells because they tend to develop in a relatively clearer way. Colon cancer usually originates from intestinal stem cells (ISCs), which have a long lifespan and help us to renew the gut tissue in a timely manner. Over time, ISC accumulate a number of cancer-associated mutations and form polyps, which have the potential to develop further into colon cancer.

  So how does this gradual development of cancerous changes escape the immune system? The authors tried to culture some mini colon tumour models in vitro and then transplanted the tumours into mice. These tumours each carried some common cancer-causing mutations, such as KRAS, p53 or APC mutations. After entering the mice, the tumours gradually elevated the expression level of SOX17.

  Normally, SOX17 is active during embryonic development, helping gut and blood vessel formation. In cancer cells, however, the role of SOX17 changes, and its aberrant expression causes the production of certain proteins to be blocked, including the interferon gamma receptor. Large amounts of SOX17 bind to the promoter region of the gene encoding the interferon gamma receptor, directly blocking its expression.

  In addition to the interferon receptor being affected, the overall microenvironment of the tumour is also gradually altered, and the authors looked at what the difference would be between tumours expressing or not expressing SOX17; for about 2 weeks, both tumours were infiltrated with ^CD4+ and ^CD8+ T cells, although by week 4, in the tumour that was expressing SOX17, the T cells were gradually moving towards depletion, and at the same time, T-cells were killing was diminished, which gave the tumours a better chance of survival.

  In addition to the microenvironment becoming more suitable for tumour survival, the loss of the cell's interferon gamma receptor also means that it no longer receives interferon signals, which is another big blow to the immune system. Firstly, the interferon signalling pathway would have delivered the message of programmed cell death, and cancer cells expressing SOX17 no longer respond to this instruction, which allows them to avoid the end of death. On top of this, cancer cells down-regulate antigen-presenting cells on their surface, making it harder for immune cells to detect their presence.

  With all these effects, the SOX17-expressing cancer cells are then able to continue to develop and grow into larger tumours. The authors note that this finding also opens up new potential strategies for tumour prevention, and if we can turn off SOX17 expression, we may be able to wipe them out in one fell swoop in the early stages of cancer.