1. Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers
- Author
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John R. Wunderlich, Paul F. Robbins, Anna Pasetto, Li Jia, Mona El-Gamil, Gal Cafri, Maria R. Parkhurst, Eric Tran, Yong F. Li, Lien T. Ngo, Winifred Lo, Robert Somerville, Mojgan Ahmadzadeh, Jessica S. Crystal, Todd D. Prickett, Gabriel Ivey, Satyajit Ray, Frank J. Lowery, Rami Yossef, Abraham Sachs, Steven A. Rosenberg, Almin Lalani, Scott Kivitz, Eric M. Groh, Drew C. Deniger, Parisa Malekzadeh, Stephanie L. Goff, and Jared J. Gartner
- Subjects
0301 basic medicine ,Somatic cell ,medicine.medical_treatment ,T cell ,Receptors, Antigen, T-Cell ,medicine.disease_cause ,Lymphocyte Activation ,Article ,03 medical and health sciences ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,Antigen ,Antigens, Neoplasm ,T-Lymphocyte Subsets ,medicine ,Biomarkers, Tumor ,Humans ,Gene ,Exome sequencing ,Gastrointestinal Neoplasms ,Mutation ,Tumor-infiltrating lymphocytes ,business.industry ,Immunotherapy ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Disease Susceptibility ,business - Abstract
Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-reactive tumor-infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen-reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of in vitro T-cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic nonsynonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell-based immunotherapies for patients bearing these cancers. Significance: TILs cultured from 62 of 75 (83%) patients with gastrointestinal cancers recognized neoantigens encoded by 1.6% of somatic mutations expressed by autologous tumor cells, and 99% of the neoantigenic determinants appeared to be unique and not shared between patients. This article is highlighted in the In This Issue feature, p. 983
- Published
- 2018