PD-L1 can repress the CTLA4 axis to stimulate an immune response.

  • 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.

Zhao Y, Lee CK, Lin CH, Gassen RB, Xu X, Huang Z, et al. PD-L1:CD80 cis-heterodimer triggers the co-stimulatory receptor CD28 while repressing the inhibitory PD-1 and CTLA-4 pathways. Immunity 2019 Nov 19 [Epub ahead of print].

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