A soluble form of CD80 delays tumor growth and promotes TIL activation by combining checkpoint blockade and costimulation mechanisms

Identification: 2003


Description

A soluble form of CD80 delays tumor growth and promotes TIL activation by combining checkpoint blockade and costimulation mechanisms

Lucas Horn, Tiha Long, Ryan Atkinson, Suzanne Ostrand-Rosenberg

Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD

Tumor cells employ various immune suppressive strategies to overcome anti-tumor immunity. One such method is mediated by programmed death ligand-1 (PDL1), which triggers apoptotic death or anergy upon binding programmed death-1 (PD1) on T cells. In vitro cellular studies with human and mouse PDL1+ tumor cells demonstrated that a soluble form of the costimulatory molecule CD80 prevented PDL1-mediated immune suppression and restored T cell activation by binding PDL1 and blocking interaction with PD1. We now report that in vivo treatment of large, established PDL1+ CT26 and B16F10 tumors with CD80-Fc delays tumor growth, extends survival time, and promotes the activation of tumor-infiltrating T cells. We also clarify a mechanism by which soluble CD80 mediates its effects and report it activates transcription factors ERG1-4, NF-κB, MAPK, and Akt, downstream signaling components of the CD28 and T cell receptor pathways. Although soluble CD80 binds to CTLA4 on activated human PBMC, increasing quantities of CTLA4 antagonist antibodies in co-cultures of human PBMC and PDL1+ human tumor cells do not increase T cell activation, indicating that soluble CD80 does not suppress T cell function through CTLA4, and suggesting that CTLA4 acts as a decoy receptor for CD80, rather than functioning as a suppressive signaling receptor. Collectively, these and our earlier studies demonstrate that soluble CD80 has therapeutic efficacy in mouse tumor systems and that its effects are due to its ability to inhibit PD1-mediated suppression while concurrently activating T cells through CD28.


Credits

Credits: None available.

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