Title:
Imaging-Driven Discovery of a CTLA-4-Dependent Feedback Loop that Controls T Regulatory Cell Abundance in Tumors
Speaker: Francesco Marangoni, PhD / University of California, Irvine
Host: Booki Min, DVM, PhD
Topic:
Although checkpoint blockade immunotherapy extends overall and progression-free survival for some oncologic patients, its efficacy is still limited to a minority of cases and of tumor types. We hypothesized that immunotherapy failure can at least in part be ascribed to the functional enhancement of tumor-associated T regulatory cells (Treg). We characterized the spatio-temporal dynamics of antigen-mediated Treg activation in tumors using intravital microscopy, and discovered that CTLA-4 blockade directly enhances the activation and proliferation of tumor-associated Treg. Mechanistically, anti-CTLA-4 antibodies disrupt a CD28-dependent feedback loop that adjusts Treg proliferation to the amount of co-stimulatory ligands expressed in the tumor microenvironment. Inhibition of Treg activation greatly enhanced the therapeutic efficacy of CTLA-4 blockade. We thus discovered unwanted immunosuppression triggered by CTLA-4 blockade that may explain the lack of therapeutic efficacy in many patients.