Cis interactions make immune checkpoint blockade more trans-parent

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Science Immunology  03 Jan 2020:
Vol. 5, Issue 43, eaba7107
DOI: 10.1126/sciimmunol.aba7107


PD-L1:CD80 cis-heterodimer formation preferentially blocks CTLA-4 trans-signaling while allowing CD28-mediated effector T cell activation.

Combinatorial immune checkpoint blockade (ICB) targeting both CTLA-4 and the PD-1/PD-ligand axis improves anti-tumor immune responses relative to ICB monotherapy. To facilitate rational approaches to ICB, it is essential to dissect the complex interface cross-talk between three significant receptors on T cells (PD-1, CTLA-4, and CD28) and their major ligands on APCs (PD-L1 and CD80 or CD86). In trans interactions, CTLA-4 is known to outcompete CD28 for CD80 and CD86 binding. CTLA-4 also indirectly depletes CD80 and CD86 via trans-endocytosis, indirectly blocking CD28 activation. Whereas PD-L1 conventionally binds PD-1 across membranes (“in trans”), prior work has also shown that where CD80 is significantly expressed, PD-L1 and CD80 are prone to heterodimerize (cis-heterodimerization), disrupting trans PD-L1:PD-1 interactions and thereby indirectly reducing downstream PD-1-mediated exhaustion in conventional effector T cells.

Zhao et al. used elegant reductionist approaches including in vitro lipid bilayers and APC-T cell MLR to delineate another feature of this heterodimerization—namely, how PD-L1:CD80 cis-heterodimerization modifies CD80 trans-interactions with CD28 and CTLA-4. This sheds some important light on potential mechanisms underpinning combinatorial ICB synergy. Their data suggest that although PD-L1:CD80 cis-heterodimerization does not affect the ability of CD80 to bind to CD28, PD-L1:CD80 cis-heterodimer generation does reduce CD80:CD80 homodimerization, which in turn disrupts CD80:CTLA-4 trans- interactions and subsequent CD80 trans- endocytosis. Using a specific blocking antibody against PD-L1:CD80 cis-interaction in T cell:APC MLR studies, the authors demonstrated depletion of CD80 expression on APCs that was reversed by treatment with the anti–CTLA-4 antibody ipilimumab. PD-L1:CD80 cis-heterodimerization thus selectively weakens CTLA-4:CD80 over CD80:CD28 trans-interactions and reduces CTLA-4 mediated CD80 trans-endocytosis, with the net effect of enhancing APC-mediated T cell stimulation and reducing Treg activation. Using in vivo murine breast and colon cancer models, the authors showed that anti–PD-L1 (but not anti–PD-1) monotherapy associated with a significant decrease in CD80 ligand expression on tumor-infiltrating APCs. Collectively, the data present the novel concept that relative ratios of PD-ligands and CD80 on APCs may indirectly influence anti–CTLA-4 monotherapy and provide a mechanistic rationale for the efficacy of combinatorial ICB immunotherapy.

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