Mining Exomic Sequencing Data to Identify Mutated Antigens Recognized by Adoptively Transferred Tumor-reactive T cells

By P. Robbins, Yong-Chen Lu, M. El-Gamil, Yong F Li, Colin Gross, J. Gartner, Jimmy Lin, J. Teer, P. Cliften, Eric Tycksen and 2 more. Nature Medicine, 2013

1,116 citations recorded by the source corpus.

Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex–binding algorithm for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/ee5d73a3e70ebc9bff397de2a61f1a2a540e782f

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Citations in the corpus

A comprehensive review and performance evaluation of bioinformatics tools for HLA class I peptide-binding prediction (2020, background): “Up until recently, most of these data have been generated using in vitro binding assays [15, 16], but the use of mass spectrometry (MS)-based identification of purified HLA-binding peptides has now come into the forefront [17–19].”
Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis (2016, positive): “Several recent clinical studies now demonstrate that T cells that recognize tumor-specific mutant antigens can be functionally rescued by checkpoint blockade (PD1, PD-L1, CTLA4) or expansion in vitro (Gubin et al., 2014; Lu et al., 2013; Rizvi et al., 2015; Robbins et al., 2013; Snyder et al., 2014;”
New insights into cancer immunoediting and its three component phases — elimination, equilibrium and escape (2014, positive): “Subsequent work by others has indeed extended this finding to human cancer patients [12,13].”
Immune escape mechanisms as a guide for cancer immunotherapy (2014, background): “Recent studies have now demonstrated that T cells recognizing neoantigens infiltrate tumor tissue and can mediate strong tumor regressions after ex vivo expansion and adoptive transfer (11-13).”
Genomic Classification of Cutaneous Melanoma (2015, background): “Nonetheless, despite these data, the question of whether specific mutated melanoma antigens are responsible for differences in the degree of tumor infiltration by lymphocytes is an area of active investigation (Robbins et al., 2013; Snyder et al., 2014).”
Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive Melanoma (2013, methodology): “After acceptance of this manuscript, Robbins et al (22) demonstrated how mutated antigens that are recognized by adoptively transferred tumor-reactive T cells can also be identified with the use of exomic sequencing data.”