CD137-CRDI is not necessary in the role of contacting its natural ligand.

Immune checkpoint inhibitors result in impressive clinical responses and are expanding to treat a wide variety of tumors. One common problem is low responses from current clinical trials that only benefit a fraction of patients. One key promising direction is combination therapy to increase clinical benefit. CD137, a well-defined antitumor target, can cause strong co-stimulating activity and break immune tolerance. In this study, the role of CD137-CRDI (cysteine rich domain I) in the binding of CD137-CD137L was further investigated based on our previous work. The results revealed that CRDI-mediated limited CD137 assembly without relying on CD137L. Furthermore, CRDI was not involved in direct contact with CD137L in either mice or humans. Isolated mouse CRDII and human CRDII+CRDIII were proven to be the minimum unit for interface with their respective ligands. Fine-tuning of this signaling may improve CD137-targeting strategy.