A study explains why some cancers do not respond to anti-PD-1

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Scientists at the Georgetown University Medical Center (United States) have discovered a mechanism that could explain why some cancers do not respond to a widely used form of immunotherapy, control point inhibitors or anti-PD-1. In addition, researchers say they have found a way to solve this lack of response.

His work shows, in animal models and samples of patient tumors, that the state of T cells before anti-PD-1 therapy is a crucial determinant of responsiveness. According to Samir Khleif, one of the team members, “if the immune cells are not in the proper activation state, treatment with anti-PD-1 brings these T cells to a dysfunctional and non-reprogrammable state, inducing resistance to immunological therapy. “

To prevent the immune system from attacking normal cells, the body has a way of protecting these cells from immune attack. Cancer cells often adopt this system of checkpoints in order to curb immune surveillance to protect themselves and grow. Control point inhibitors release those ‘brakes’.

These inhibitors target molecules, such as PD-1 (programmed cell death 1), which is located on the surface of a T cell, and the molecule, PDL-1 that is present in tumor cells and binds to PD -one. This PD-1 / PDL-1 pairing inhibits the normal functioning of T cells that would otherwise attack the cancer cell. Therefore, medications, in the form of antibodies that bind to PD-1 or PDL-1, work to eliminate that protection, allowing T cells to recognize and attack the tumor.

It is known that tumors that respond more easily to control point inhibitors are those that have already been compromised with the immune system, such as melanoma and cancers that express many mutations. The question has been why immunotherapeutic agents do not work in immunologically ‘silent’ tumors. This discovery sheds some light on the subject.

The team was also able to find a strategy to overcome that resistance to immunotherapy. “When we first activate T cells by using a simple vaccine, or eliminate dysfunctional T cells, we find that control point inhibitor therapy works better,” they detail.


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