Diversity at least among cancer cells is not a good thing. Now, research from the Weizmann Institute of Science in Rehovot shows that in melanoma, tumors with cells that have differentiated into more diverse subtypes are less likely to be affected by the immune system, thus reducing the chance that immunotherapy will be effective.

The findings of this research, published in Cell, may provide better tools for designing personalized protocols for cancer patients, as well as pointing toward new avenues of research into anti-cancer vaccines.

Prof. Yardena Samuels of the Institutes Department of Molecular Cell Biology wanted to know why, despite the fact that cancer deaths from melanoma have dropped in recent years (thanks to new immunotherapy treatments), many patients do not respond to therapy. The reasons have not been clear, though the leading hypothesis, supported by a few studies, has been that tumors with more mutations are more likely to respond to immunotherapy. Some patients even spend large sums to undergo radiation or chemical treatments to increase tumor mutations, but a causal relationship between the two has not yet been proven.

Samuels and her colleagues were intrigued by studies that suggested a different possible correlation one between heterogeneity (that is, the genetic diversity among tumor cells) and the response to therapy. To investigate this theory, however, the team had to develop a new experimental system to check exactly which factors play a role.

We showed the difference between two extremes highly homogeneous and highly heterogeneous but most cancers fall somewhere in between, says Dr. Bartok. To systematically generate tumors with intermediate levels of genetic heterogeneity, we created a phylogenetic tree of the parental heterogeneous line, and mapped out how subtypes appear over time.

Then we created cocktails of homogeneous cell lines based on this tree, with more or less heterogeneous combinations of cells, and injected them into mice.

As predicted, the more homogeneous the cell cocktail, the easier it was for the mices immune systems to eradicate the cancer, whereas the more heterogeneous the tumors were, the more aggressive they became.

Ultimately, we intend to use the experimental system we created to work on developing applicable personalized protocols for cancer patients, Samuels said.

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