The problem with relapsers’ cancer cells is they evade patients’ NK cells by making themselves effectively invisible.  Because the patient’s immune system cannot see them, it cannot kill them.  Understanding the problem requires a deeper understanding of NK cell biology.  In nature, resting NK cells must become activated NK cells to kill cancer cells.  To prevent uncontrolled killing of normal cells, multiple signals are required for this conversion.  We have shown that these signals are divided into two stages of activation.  Stage 1 (S1) moves the resting NK cell to a state of priming that makes it ready to be triggered by a cancer cell. Many cancers fail to provide the signals need to prime. Once primed the NK cells need further signals to move to Stage 2 (S2) and trigger the killing mechanism. The signalling molecules need to drive the NK cells to S1 and S2 are located on the cancer cell.  These are the sets of molecules expressed by a survivor’s cancer cells and why the patient’s immune system can eliminate residual disease. 

Cancer cells are simply normal cells that have mutated to lose the ability to die naturally. The vast majority are killed by chemotherapy or radiotherapy, but some acquire more mutations that make them resistant.  A common mutation is to downregulate the priming molecules on the cancer cell surface.  When the patient’s resting NK cells fail to receive priming signals, they never achieve S1 of activation.  As such, they cannot progress to S2 and kill the cancer cell.  The cancer cell could equally mutate to retain the priming signals but lose the ability to trigger lysis (S2), in which case the cancer would still evade killing. For reasons that we don’t understand, most cancer cells retain triggering ability but fail to prime NK cells.  In this dichotomy lies the opportunity….

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