Major finding: Binding of PD-L1 to CD80 in cis disrupts its binding to PD-1 and restricts PD-1–mediated T-cell suppression.
Concept: Knock-in mice with mutated PD-L1 or CD80 exhibited impaired PD-L1/CD80 binding and reduced T-cell function.
Impact: Targeting cis-PD-L1/CD80 interactions might provide new therapeutic approaches for cancer.
Immunotherapy based on targeting immune checkpoint receptors such as PD-1 and CTLA4 has shown clinical benefit in several types of cancer. Blocking these inhibitors enables the activation of tumor-specific T cells, though it can also lead to the activation of autoreactive T cells. PD-1 interaction with either PD-L1 or PD-L2 promotes T-cell inhibition. CTLA4 interaction can lead to inhibition of T cells through binding to CD80 or CD86, whereas CD80 and CD86 can activate T cells through binding to the costimulatory protein CD28. Interactions between PD-L1 and CD80 have also been reported, but the outcome of these interactions is not well defined. Sugiura and colleagues investigated the cis (within the same cell) and trans (between T cells and antigen-presenting cells such as dendritic cells) interactions of checkpoint inhibitory molecules and found that CD80 interacts in cis with PD-L1 on primary activated dendritic cells. This interaction impaired binding of PD-L1 to PD-1 and subsequently abrogated PD-1–mediated T-cell suppression in both mice and human orthologs. The interaction of CD80 with PD-L1 did not interfere with binding of CD80 to CD28 or CTLA4. Mice with knock-in mutations in PD-L1 or CD80 that prevented cis interactions showed impaired PD-L1/CD80 interaction and defective T-cell responses as shown by reduced T-cell production of IFNγ and IL2 following antigen stimulation. Initiation of antitumor immune response was also attenuated when CD80/PD-L1 cis interactions were disrupted. Mutated mice also showed reduced T-cell function in an autoimmunity model. Collectively, these results indicate that cis PD-L1/CD80 interactions prevent PD-L1/PD-1 interaction and promote T-cell responses against foreign, tumor-associated, and self antigens. These results show how optimal T-cell responses are regulated by costimulatory and coinhibitory signals and provide insights that might guide optimization of immune checkpoint blockade therapy.
Notes
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
- ©2019 American Association for Cancer Research.
Volume 9, Issue 7
