When less is more in the immune recognition of cancer

What is it about?

There was a revolution in cancer therapy in the early 21st century. Cancer immunotherapy, which is based on amplifying anticancer immunity made it possible to cure millions of people with advanced cancer. But at least half of them do not respond to the treatment. Identifying these patients before starting the therapy is crucial because these patients could be involved in clinical studies instead of taking an expensive drug, which is ineffective in their case. What lies behind treatment failure? Human leukocyte antigen (HLA) molecules make cancer cells visible to the immune system by presenting mutated protein fragments on their surface. These molecules are extremely variable and, thus, potentially differ between cancer patients. Certain variants can present much more mutated protein fragments. One would expect that patients carrying these variants respond to immunotherapy because their immune systems are more likely to identify cancer cells. But researchers in Szeged, Hungary found exactly the opposite. What can be the explanation? HLA variants that present many mutated protein fragments also present a high number of normal, non-mutated ones. As mutant and normal proteins are frequently very similar, the immune system is unable to differentiate between cancer and normal human cells. Consequently, the immune system tolerates tumor cells. But why are these HLA variants prevalent, if they hinder anticancer immune response? The same research group reported that these variants can induce an effective immune response against a higher number of viral infections and, thus, they are more prevalent in countries associated with many viral infections (for example the tropical regions). As viral proteins are much more different from human ones, the immune system can easily recognize them. However, as a potential negative trade-off, the anticancer immune response could be less effective in these individuals.

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Photo by Scott Webb on Unsplash

Photo by Scott Webb on Unsplash

Why is it important?

Tumor immunotherapy augments the immune recognition of cancer cells, which could destroy even metastatic tumors. While it was a huge step forward in the treatment of cancer patients, a notable fraction of them does not respond to the therapy. Consequently, it is of utmost importance to identify biomarkers that can predict, which patients benefit from the treatment.