Robert Manguso

Robert Manguso

Assistant Professor of Medicine
Robert Manguso
Over the last decade, critical discoveries in immunology and cancer biology have revealed how tumors are shaped by the immune system and how they evolve to evade it. We now know that disrupting immune checkpoints such as PD-1/PDL1 can lead to T cell-mediated elimination of tumors. However, there is still a critical unmet need, as the vast majority of patients with cancer do not benefit from current immunotherapies. Our most pressing challenge is to discover the next generation of immunotherapies that can bring clinical benefit to the majority of patients.
To discover immunotherapy targets and resistance mechanisms in high throughput, we have developed an in vivo, CRISPR-based genetic screening system to identify genes that regulate tumor cell sensitivity to immunotherapy (Manguso et al, Nature 2017). We genetically modify mouse cancer cell lines that can be transplanted into animals and used as immunotherapy models. After delivery of Cas9 and libraries of single guide RNAs (sgRNAs), we implant pools of modified tumor cells into animals that are treated with immunotherapy. In a single experiment we can determine genes that, when deleted, increase or decrease sensitivity to immunotherapy. This strategy has enabled the rapid and simultaneous identification of new targets and resistance mechanisms that are potent regulators of anti-tumor immunity.
This powerful, unbiased discovery system allows us to identify targets and resistance mechanisms with no previously identified roles in immunotherapy such as PTPN2, a phosphatase that dampens IFN signaling (Manguso et al, Nature 2017); ADAR1, an adenosine deaminase that prevents the sensing of endogenous dsRNA (Ishizuka and Manguso, Nature 2019); SETDB1, a histone lysine methyltransferase that represses the expression of endogenous retroviruses (Griffin et al, Nature 2021); and HLA-E, a non-classical MHC-I that serves as a T and NK cells inhibitory ligand. Previously, these genes were not known or prioritized targets in immuno-oncology, but our unbiased approach enables discoveries that would have otherwise been unlikely
We have demonstrated that in vivo genetic screens are a powerful way to discover new targets and probe the interaction of tumor cells with the host immune system. We can now broadly apply these tools to advance our understanding of how immunotherapy works, why it may fail, and how we can improve it.
Ongoing projects in the lab include:
1. Immunotherapy target discovery and mechanism of action studies using several well-characterized mouse cancer models
2. Screens for pathways involved in acquired resistance to immunotherapy
3. Identify mechanism to improve the function and persistence of CAR T cells and other cell therapy approaches
These projects will define new ways to generate anti-tumor immune responses, reveal pathways that can be targeted to enhance these responses across cancer types, and anticipate and overcome the mechanisms by which tumors will become resistant. More broadly, these studies will improve our understanding of how tumors evolve under the selective pressure of immune surveillance and enable the development of more effective therapeutics.

Contact Information

Massachusetts General Hospital East
149 13th Street
Charlestown, MA 02129