PD-L1/CD80 cis Interactions Disrupt PD-L1–PD-1 Binding and Promote T-cell Function

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.

Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science 2019;364:558–66.

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.