Alternative tumour-specific antigens

Smith, Christof C.; Selitsky, Sara R.; Chai, Shengjie; Armistead, Paul M.; Vincent, Benjamin G.; Serody, Jonathan S.

doi:10.1038/s41568-019-0162-4

Cited by 265 publications

(242 citation statements)

References 202 publications

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“…Interestingly, it has been found that some human cancer-specific antigens, silent in normal tissues, are translated from alternative open reading frames (AltORFs) (Wang et al, 1996(Wang et al, , 1998Rosenberg et al, 2002;Mandic et al, 2003;Slager et al, 2003). These neoantigens are promising targets for the development of antitumour immunotherapies with a potentially broader coverage of patients (Smith et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

New insights into the evolutionary features of viral overlapping genes by discriminant analysis

Pavesi

2020

Virology

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Please cite this article as: Pavesi, A., New insights into the evolutionary features of viral overlapping genes by discriminant analysis, Virology, https://doi. AbstractOverlapping genes originate by a mechanism of overprinting, in which nucleotide substitutions in a pre-existing frame induce the expression of a de novo protein from an alternative frame. In this study, I assembled a dataset of 319 viral overlapping genes, which included 82 overlaps whose expression is experimentally known and the respective 237 homologs. Principal component analysis revealed that overlapping genes have a common pattern of nucleotide and amino acid composition.Discriminant analysis separated overlapping from non-overlapping genes with an accuracy of 97%.When applied to overlapping genes with known genealogy, it separated ancestral from de novo frames with an accuracy close to 100%. This high discriminant power was crucial to computationally design variants of de novo viral proteins known to possess selective anticancer toxicity (apoptin) or protection against neurodegeneration (X protein), as well as to detect two new potential overlapping genes in the genome of the new coronavirus SARS-CoV-2.

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Section: Introductionmentioning

confidence: 99%

New insights into the evolutionary features of viral overlapping genes by discriminant analysis

Pavesi

2020

Virology

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“…The successful clinical implementation of checkpoint inhibitors and CAR-T cells in the routine treatment of various tumor entities has heralded a new era of immunotherapies in cancer [108,109]. Tumor-specific neoantigens derived from fusion oncogene breakpoint regions have attracted great scientific interest for many years, especially as an alternative to singlenucleotide variant-derived tumor-specific antigens [110]. Recently, gene-fusion-derived neoantigens were found to induce tumor-specific T cells and facilitated a complete response in a head and neck-cancer patient treated with immune checkpoint inhibitors despite an overall low tumor mutational burden [111].…”

Section: Targeting Fusion Oncoprotein-specific Neoantigens By Immunotmentioning

confidence: 99%

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

Knott

Hölting²,

Ohmura³

et al. 2019

Cancer Metastasis Rev

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While sarcomas account for approximately 1% of malignant tumors of adults, they are particularly more common in children and adolescents affected by cancer. In contrast to malignancies that occur in later stages of life, childhood tumors, including sarcoma, are characterized by a striking paucity of somatic mutations. However, entity-defining fusion oncogenes acting as the main oncogenic driver mutations are frequently found in pediatric bone and soft-tissue sarcomas such as Ewing sarcoma (EWSR1-FLI1), alveolar rhabdomyosarcoma (PAX3/7-FOXO1), and synovial sarcoma (SS18-SSX1/2/4). Since strong oncogene-dependency has been demonstrated in these entities, direct pharmacological targeting of these fusion oncogenes has been excessively attempted, thus far, with limited success. Despite apparent challenges, our increasing understanding of the neomorphic features of these fusion oncogenes in conjunction with rapid technological advances will likely enable the development of new strategies to therapeutically exploit these neomorphic features and to ultimately turn the "undruggable" into first-line target structures. In this review, we provide a broad overview of the current literature on targeting neomorphic features of fusion oncogenes found in Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma, and give a perspective for future developments.

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“…We propose that two elements should be taken into consideration. First, we believe that searches limited to exonic TSAs considerably underestimate the diversity of the TSA repertoire (47). According to initial analyses of primary acute lymphoblastic leukemia samples, the vast majority of TSAs are aeTSAs derived from unmutated allegedly non-coding sequences.…”

Section: Low Accuracymentioning

confidence: 99%

The Genomic Landscape of Antigenic Targets for T Cell-Based Leukemia Immunotherapy

2019

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Intensive fundamental and clinical research in cancer immunotherapy has led to the emergence and evolution of two parallel universes with surprisingly little interactions: the realm of hematologic malignancies and that of solid tumors. Treatment of hematologic cancers using allogeneic hematopoietic cell transplantation (AHCT) serendipitously led to the discovery that T cells specific for minor histocompatibility antigens (MiHAs) could cure hematopoietic cancers. Besides, studies based on treatment of solid tumor with ex vivo-expanded tumor infiltrating lymphocytes or immune checkpoint therapy demonstrated that anti-tumor responses could be achieved by targeting tumor-specific antigens (TSAs). It is our contention that much insight can be gained by sharing the tremendous amount of data generated in the two-abovementioned universes. Our perspective article has two specific goals. First, to discuss the value of methods currently used for MiHA and TSA discovery and to explain the key role of mass spectrometry analyses in this process. Second, to demonstrate the importance of broadening the scope of TSA discovery efforts beyond classic annotated protein-coding genomic sequences.

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Alternative tumour-specific antigens

Cited by 265 publications

References 202 publications

New insights into the evolutionary features of viral overlapping genes by discriminant analysis

New insights into the evolutionary features of viral overlapping genes by discriminant analysis

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

The Genomic Landscape of Antigenic Targets for T Cell-Based Leukemia Immunotherapy

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