Francesca Smylie Gazzaniga, PhD, CRI CLIP Investigator Massachusetts General Hospital Area of Research: All Cancers Immune checkpoint inhibitors (ICI) are standard treatment for more than 20 tumor types, yet only 20% of patients respond. ICIs induce T cell-mediated tumor killing by blocking interactions between Programmed Cell Death Protein 1 (PD-1) and Programmed Cell Death Ligand 1 (PD-L1) which disrupts inhibitory signaling on immune cells. Paradoxically, the efficacy of ICIs is influenced by the gut microbiota. In 30% of melanoma patients who did not respond to ICI, fecal transplants from melanoma patients who did respond conferred ICI treatment-responsiveness. The mechanisms by which gut microbiota regulate this process, however, are largely unknown. Recently, Dr. Gazzaniga showed that gut microbiota promotes anti-tumor responses to ICI by suppressing Programmed Cell Death Ligand 2 (PD-L2) on dendritic cells and Repulsive Guidance Molecule b (RGMb) on CD8+ T cells. Furthermore, combined anti-PD-L2 or anti-RGMb treatment with anti-PD-L1 or anti-PD-1 overcame microbiome-dependent resistance to monotherapy in many preclinical tumor models. However, what tumor types are most likely to benefit from this combination therapy and whether RGMB or PD-L2 expression correlates with response to ICI in patients is unknown. In this proposal, the overall objectives are to determine the efficacy of combining RGMb/PD-L2 blockade with PD-1/PD-L1 blockade in multiple cancers and with multiple patient microbiomes (Aim 1) and to validate whether PD-L2 and RGMb expression can be used as biomarkers to predict response to cancer immunotherapy (Aim 2). This research will have a positive translational impact by evaluating the efficacy of a novel immunotherapy in preclinical models and by defining new biomarkers for anti-tumor immunity. Projects and Grants Targeting PD-L2/RGMb interactions to enhance the efficacy of cancer immunotherapy Massachusetts General Hospital | All Cancers | 2024
