Targeted blockade of PD-1 using immune checkpoint inhibitor can activate T cells to destroy tumors. PD-1 is thought to act primarily on the effector phase of the T cell response, rather than on the activation phase of the T cell response. It is still unclear as to how PD-1 is restricted during the activation phase.

In a new study, researchers from the University of Tokushima, Japan, demonstrated that CD80 cis-acting with PD-L1 on the surface of antigen-presenting cells (APCs), thereby disrupting PD-L1/PD-1 binding. Subsequently, when APC expressed a large amount of CD80, PD-L1 was unable to bind to PD-1 to inhibit T cell activation. Tumor immune responses and autoimmune responses are greatly attenuated by PD-1 by knocking in mice that cannot occur using PD-L1/CD80 cis-interaction. These findings indicate that CD80 on the surface of APC limits PD-1 co-suppression signals while promoting CD28-mediated co-stimulation, thus highlighting the key components that induce optimal immune responses. The relevant research results were published online in the Science Journal on April 18, 2019.

The identification of PD-L1/CD80 cis-interactions has highlighted the complexity of signaling in the B7/CD28 family and has been suggested to explain the differences between PD-1 antibodies and PD-L1 antibodies in cancer immunotherapy. For example, it has been suggested that PD-L1 antibodies may provide better clinical efficacy than PD-1 antibodies because they are capable of blocking inhibition signals by PD-L1 and CD80 in addition to PD-1. However, to date, no significant difference has been found in the clinical efficacy between the PD-1 antibody and the PD-L1 antibody, and the true importance of the PD-L1/CD80 cis-interaction occurring between T cells and APC is difficult to be made clear. In this new study, these researchers demonstrated that CD80 cis-acting with PD-L1 on the same APC surface and inhibiting PD-L1 binding to PD-1 and inhibiting T cell activation. Nonetheless, these findings do not rule out the possible cis-interactions and functions between PD-L1 and CD80 under certain conditions or in certain model systems.

Ostrand-Rosenberg and colleagues have reported that overexpression of CD80 on the surface of tumor cells expressing PD-L1 attenuates PD-1 binding to tumors. Based on this finding, they proposed the use of CD80 soluble protein (CD80-Ig) for cancer immunotherapy because CD80-Ig may block the inhibition signal by PD-L1/CD80 and PD-L1/PD-1. However, the pattern of interaction between PD-L1 and CD80 was not clearly defined in these studies, and the interaction of CD80 and PD-L1 under physiological conditions was not confirmed. Another recent study has reported that co-overexpression of CD80 and PD-L1 on the same cell results in a cis-interaction between them, and competition between PD-1 and CD80 to bind PD-L1 is also observed at the protein level. However, the functional consequences of this competition have not been explored, and their interaction under physiological conditions has not been confirmed. Furthermore, the importance of PD-L1/CD80 cis-interaction in inducing and/or modulating immune responses is unclear.

In this new study, these researchers reported that in primary dendritic cells, CD80, which binds cis to PD-L1, strongly interferes with PD-L1/PD-1 binding. In addition, they observed that PD-L1/CD80 cis-interaction strongly abolished PD-1 function. They developed two knock-in mouse strains in which the PD-L1/CD80 cis-acting interaction was specifically attenuated and they found immunity against foreign antigens, tumor-associated antigens and autoantigens. During the reaction, PD-1 function is continuously limited by the PD-L1/CD80 cis-interaction. Interestingly, the PD-1 binding capacity of dendritic cells was regulated differently depending on the TLR agonist used, suggesting that PD-1 may alleviate T cell immune reaction against pathogens to varying degrees depending on the molecular pattern associated with the pathogen.

Although PD-1 is a potent co-repressor receptor, it can strongly inactivate T cells, especially during the autoimmune disease or cancer response phase, but PD-1 does not necessarily eliminate all T cells reaction, which indicates that the function of PD-1 may be limited by some mechanism. To date, the restriction of PD-1 function during the immune activation phase is usually explained by PD-1 expression on the surface of effector T cells. However, it has been found that PD-1 appears on the surface of T cells within hours of antigen stimulation, which makes delayed expression of PD-1 less likely to be a core mechanism. The findings of this new study reveal a rational and detailed mechanism by which CD80 enhances T cell activation not only by mediating CD28 costimulatory signals, but also by attenuating PD-1-driven co-suppression signals. In vivo studies using Cd274Y56A and Cd80L107E mice have shown that PD-L1/CD80 cis-interaction limiting PD-1 function is critical for inducing optimal immune responses against foreign antigens, tumor-associated antigens and autoantigens. Given the success of cancer immunotherapy targeting PD-1, the number of clinical trials in this area is expanding. Thus, targeted manipulation of PD-L1/CD80 cis-interactions may lead to new therapeutic opportunities for the treatment of cancer, autoimmune diseases and chronic inflammation.

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Daisuke Sugiura et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science, 2019, doi:10.1126/science.aav7062.

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