Major Finding: PD-L1 can repress the CTLA4 axis to stimulate an immune response.
Mechanism: PD-L1–CD80 binding prevents CTLA4–CD80 interactions without blocking CD80-mediated CD28 activation.
Impact: This study provides mechanistic insight into the synergy between PD-1/PD-L1 and CTLA4 blockade.
Combined immunotherapy using anti–PD-L1 or anti–PD-1 in conjunction with anti-CTLA4 has been observed in some clinical and preclinical studies to outperform single-agent immunotherapy treatment, but the molecular mechanisms are not well understood. Zhao and colleagues found evidence that PD-L1 and the costimulatory protein CD80 strongly interact in cis, but not in trans, on cell membranes, and the anti–PD-L1 drug atezolizumab abrograted this binding in vitro. Further experiments showed that PD-L1–CD80 interactions in cis inhibited trans interactions between PD-L1 and PD-1, diminishing PD-L1–PD-1 signaling. This interaction between PD-L1 and CD80 in cis did not have an impact on CD80's binding to and activation of its receptor, CD28; however, it did reduce CD80–CTLA4 binding. Additional experiments suggested that the inhibitory effect of PD-L1–CD80 interactions in cis on CD80–CTLA4 binding did not depend on occlusion of CD80's CTLA4 binding site, but rather relied on preventing CD80 homodimerization. The presence of PD-L1 in cis to CD80 obstructed the canonical CTLA4-mediated depletion of CD80 from antigen-presenting cells (APC) via trans endocytosis, and atezolizumab treatment caused CTLA4-dependent CD80 depletion on APCs. In a mouse model of breast cancer, treatment with anti–PD-L1, but not anti–PD-1, caused a reduction in CD80 presentation on APCs. Collectively, these findings support a model in which the mechanism of clinical utility of anti–PD-L1 treatment may not be limited to interference with interactions between PD-1 and PD-L1, but rather may also involve disruption of PD-L1–CD80 heterodimers, promoting the formation of CD80–CTLA4 interactions, resulting in the depletion of CD80 from APCs and consequently reducing costimulation by CD28.
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 10, Issue 1
