Unleashing the immune system on cancer

There has been a much awaited step forward in cancer therapy: by removing roadblocks on the path of patients’ immune response, the management of some types of cancer (e.g., melanoma, etc.) has improved.  These roadblocks or checkpoints, as scientists call them, are necessary so that our immune system “knows” when to stop its response to a trigger. The trigger could be a protein that the immune system considers “foreign” to the organism.  Some cancers express such “foreign” proteins, since mutations may transform our normal proteins into “foreign” proteins that are not recognized by the immune system.  If this happens, the immune system can attack the cancer cells expressing “foreign” proteins, and eventually kill these cells.  The caveat is that some tumor cells evade the immune response because they “utilize” the natural checkpoints of the immune system to stop its response. Such cancers are spared by the immune system, and continue to grow unperturbed.  

Currently, immunotherapy targets two checkpoints that are utilized by cancers to evade  immune response.  In successful cases, the untethered immune system of the cancer patient is able to attack the cancer cells. However, not all patients respond to this intervention.  A recent study reveals one possible explanation for this differential response.  The authors of the study hypothesized that sometimes the suppression of the checkpoints does not work since some cancers do not express proteins that are recognized as “foreign” by the immune system. Thus, only proteins that the immune system has not encountered in the past elicit an immune response.   

The analyses revealed that the probability for a successful checkpoint therapy was higher when the cancer had more mutations. This is logical, since the more mutations a cancer cell has, the higher the chance that one or more of these mutations result in “foreign” proteins that elicit an immune response. The surprise, however, was that there were not too many common “foreign” proteins among the cancer (melanoma) patients who have benefited from the therapy. Thus, the “foreign” proteins seem to be the result of “passenger” mutations. These mutations do not contribute to the selective growth advantage of cancer cells, but accumulate along with the “driver” mutations, which do contribute to the cancer growth.  Whereas the “driver” mutations are somewhat common among some types of cancer, “passenger” mutations are diverse.

Actionable

Our understanding of why immunotherapy sometimes does not work may lead to its proper application. In the future, the decision as to whether the checkpoint therapy is appropriate for a cancer patient would be based upon the patient's mutation profile.