Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Cell. 2021 Jul 22;184(15):4032-4047.e31. doi: 10.1016/j.cell.2021.05.038. | PubMed

Sydney X Lu¹, Emma De Neef², James D Thomas³, Erich Sabio⁴, Benoit Rousseau⁵, Mathieu Gigoux⁶, David A Knorr⁵, Benjamin Greenbaum⁷, Yuval Elhanati⁷, Simon J Hogg⁸, Andrew Chow⁹, Arnab Ghosh⁹, Abigail Xie¹⁰, Dmitriy Zamarin⁹, Daniel Cui⁸, Caroline Erickson⁸, Michael Singer⁸, Hana Cho⁸, Eric Wang⁸, Bin Lu⁸, Benjamin H Durham⁸, Harshal Shah⁸, Diego Chowell¹¹, Austin M Gabel¹², Yudao Shen¹³, Jing Liu¹³, Jian Jin¹³, Matthew C Rhodes¹⁴, Richard E Taylor¹⁴, Henrik Molina¹⁵, Jedd D Wolchok⁹, Taha Merghoub⁹, Luis A Diaz Jr⁵, Omar Abdel-Wahab¹⁶, Robert K Bradley¹⁷

1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
2. Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
3. Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
4. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Center for Immunotherapy and Precision-Oncology, Cleveland Clinic, Cleveland, OH 44195, USA.
5. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
6. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
7. Department of Epidemiology and Biostatistics, Computational Oncology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
8. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
9. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
10. Medical Scientist Training Program, Weill Cornell Medical School, New York, NY 10065, USA.
11. Center for Immunotherapy and Precision-Oncology, Cleveland Clinic, Cleveland, OH 44195, USA; The Precision Immunology Institute, The Tisch Cancer Institute, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
12. Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA.
13. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
14. The Warren Family Research Center for Drug Discovery and Development and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
15. Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
16. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. Electronic address: abdelwao@mskcc.org.
17. Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: rbradley@fredhutch.org.

Abstract

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.

Presented By Sydney Ly | ORCID iD