Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma
Metrics: PDF 786 views | HTML 1221 views | ?
Paul Zolkind1, Dariusz Przybylski2, Nemanja Marjanovic2, Lan Nguyen2, Tianxiang Lin1, Tanner Johanns3,4, Anton Alexandrov4,5, Liye Zhou6, Clint T. Allen7,8, Alexander P. Miceli5, Robert D. Schreiber5, Maxim Artyomov4,5, Gavin P. Dunn4,9,* and Ravindra Uppaluri6,10,*
1Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
4Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
5Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
6Dana-Farber Cancer Institute, Boston, MA, USA
7Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD, USA
8Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA
9Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA
10Brigham and Women’s Hospital, Boston, MA, USA
Ravindra Uppaluri, email: Ravindra_Uppaluri@DFCI.Harvard.edu
Gavin P. Dunn, email: firstname.lastname@example.org
Keywords: neoantigen; immunogenomics; head and neck cancer
Received: October 17, 2017 Accepted: December 13, 2017 Published: December 28, 2017
Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1P315L (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.