publication . Other literature type . Article . 2019

Immunogenic neoantigens derived from gene fusions stimulate T cell responses.

S Ken Tian; Richard J. Wong; Diego Chowell; Ian Ganly; Justin Tepe; Marc Cohen; Luc G. T. Morris; Ronald Ghossein; Leonard H. Wexler; Zaineb Nadeem; ...
Open Access
  • Published: 22 Apr 2019
  • Publisher: Springer Science and Business Media LLC
Abstract
Anti-tumor immunity is driven by self vs. non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole genome sequencing (WGS) and RNA sequencing (RNA-seq), we identified a novel gene fusion, and demonstrated t...
Subjects
free text keywords: General Biochemistry, Genetics and Molecular Biology, General Medicine, Article, Antigen, Gene, Cancer, medicine.disease, medicine, T cell, medicine.anatomical_structure, Mutation, medicine.disease_cause, Cytotoxic T cell, Cancer research, Biology, Fusion gene, Immunotherapy, medicine.medical_treatment
Funded by
NIH| Functionalizing recurrent FAT1 mutations and deletions in oral cancer
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1K08DE024774-01
  • Funding stream: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
,
NIH| MOUSE GENETICS
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P30CA008748-43
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Elucidating genetics of response to immune checkpoint blockade in lung cancer
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01CA205426-01A1
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms Underlying Immunotherapy Efficacy and Resistance
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R35CA232097-01
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Identifying and targeting neoantigens in aggressive salivary carcinomas
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01DE027738-01
  • Funding stream: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
44 references, page 1 of 3

1 Coulie PG, Van den Eynde BJ, van der Bruggen P & Boon T Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14, 135–146, doi:10.1038/nrc3670 (2014).24457417 [OpenAIRE] [PubMed] [DOI]

2 Schreiber RD, Old LJ & Smyth MJ Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570, doi:10.1126/science.1203486 (2011).21436444 [OpenAIRE] [PubMed] [DOI]

3 Sharma P & Allison JP The future of immune checkpoint therapy. Science 348, 56–61, doi:10.1126/science.aaa8172 (2015).25838373 [OpenAIRE] [PubMed] [DOI]

4 Rosenberg SA & Restifo NP Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68, doi:10.1126/science.aaa4967 (2015).25838374 [OpenAIRE] [PubMed] [DOI]

5 Ott PA An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221, doi:10.1038/nature22991 (2017).28678778 [OpenAIRE] [PubMed] [DOI]

6 Snyder A Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371, 2189–2199, doi:10.1056/NEJMoa1406498 (2014).25409260 [OpenAIRE] [PubMed] [DOI]

7 McGranahan N Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469, doi:10.1126/science.aaf1490 (2016).26940869 [OpenAIRE] [PubMed] [DOI]

8 Samstein RM LC, Shoushtari AN, Hellmann MD, Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nature Genet. 51, 202–206 (2019).30643254 [OpenAIRE] [PubMed]

9 Ilyas S & Yang JC Landscape of Tumor Antigens in T Cell Immunotherapy. J Immunol 195, 5117–5122, doi:10.4049/jimmunol.1501657 (2015).26589749 [OpenAIRE] [PubMed] [DOI]

10 Shukla SA Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade. Cell 173, 624–633 e628, doi:10.1016/j.cell.2018.03.026 (2018).2965 6892 [OpenAIRE] [PubMed] [DOI]

11 Stevanovic S Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356, 200–205, doi:10.1126/science.aak9510 (2017).28408606 [OpenAIRE] [PubMed] [DOI]

12 Gao Q Driver Fusions and Their Implications in the Development and Treatment of Human Cancers. Cell Rep 23, 227–238 e223, doi:10.1016/j.celrep.2018.03.050 (2018).29617662 [OpenAIRE] [PubMed] [DOI]

13 Adams AK DEK promotes HPV-positive and -negative head and neck cancer cell proliferation. Oncogene 34, 868–877, doi:10.1038/onc.2014.15 (2015).24608431 [OpenAIRE] [PubMed] [DOI]

14 Qin H, Malek S, Cowell JK & Ren M Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model. Oncogene 35, 5686–5691, doi:10.1038/onc.2016.118 (2016).27065320 [OpenAIRE] [PubMed] [DOI]

15 Forbes SA COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res 45, D777–D783, doi:10.1093/nar/gkw1121 (2017).27899578 [OpenAIRE] [PubMed] [DOI]

44 references, page 1 of 3
Abstract
Anti-tumor immunity is driven by self vs. non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole genome sequencing (WGS) and RNA sequencing (RNA-seq), we identified a novel gene fusion, and demonstrated t...
Subjects
free text keywords: General Biochemistry, Genetics and Molecular Biology, General Medicine, Article, Antigen, Gene, Cancer, medicine.disease, medicine, T cell, medicine.anatomical_structure, Mutation, medicine.disease_cause, Cytotoxic T cell, Cancer research, Biology, Fusion gene, Immunotherapy, medicine.medical_treatment
Funded by
NIH| Functionalizing recurrent FAT1 mutations and deletions in oral cancer
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1K08DE024774-01
  • Funding stream: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
,
NIH| MOUSE GENETICS
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P30CA008748-43
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Elucidating genetics of response to immune checkpoint blockade in lung cancer
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01CA205426-01A1
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms Underlying Immunotherapy Efficacy and Resistance
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R35CA232097-01
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Identifying and targeting neoantigens in aggressive salivary carcinomas
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01DE027738-01
  • Funding stream: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
44 references, page 1 of 3

1 Coulie PG, Van den Eynde BJ, van der Bruggen P & Boon T Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14, 135–146, doi:10.1038/nrc3670 (2014).24457417 [OpenAIRE] [PubMed] [DOI]

2 Schreiber RD, Old LJ & Smyth MJ Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570, doi:10.1126/science.1203486 (2011).21436444 [OpenAIRE] [PubMed] [DOI]

3 Sharma P & Allison JP The future of immune checkpoint therapy. Science 348, 56–61, doi:10.1126/science.aaa8172 (2015).25838373 [OpenAIRE] [PubMed] [DOI]

4 Rosenberg SA & Restifo NP Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68, doi:10.1126/science.aaa4967 (2015).25838374 [OpenAIRE] [PubMed] [DOI]

5 Ott PA An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221, doi:10.1038/nature22991 (2017).28678778 [OpenAIRE] [PubMed] [DOI]

6 Snyder A Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371, 2189–2199, doi:10.1056/NEJMoa1406498 (2014).25409260 [OpenAIRE] [PubMed] [DOI]

7 McGranahan N Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469, doi:10.1126/science.aaf1490 (2016).26940869 [OpenAIRE] [PubMed] [DOI]

8 Samstein RM LC, Shoushtari AN, Hellmann MD, Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nature Genet. 51, 202–206 (2019).30643254 [OpenAIRE] [PubMed]

9 Ilyas S & Yang JC Landscape of Tumor Antigens in T Cell Immunotherapy. J Immunol 195, 5117–5122, doi:10.4049/jimmunol.1501657 (2015).26589749 [OpenAIRE] [PubMed] [DOI]

10 Shukla SA Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade. Cell 173, 624–633 e628, doi:10.1016/j.cell.2018.03.026 (2018).2965 6892 [OpenAIRE] [PubMed] [DOI]

11 Stevanovic S Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356, 200–205, doi:10.1126/science.aak9510 (2017).28408606 [OpenAIRE] [PubMed] [DOI]

12 Gao Q Driver Fusions and Their Implications in the Development and Treatment of Human Cancers. Cell Rep 23, 227–238 e223, doi:10.1016/j.celrep.2018.03.050 (2018).29617662 [OpenAIRE] [PubMed] [DOI]

13 Adams AK DEK promotes HPV-positive and -negative head and neck cancer cell proliferation. Oncogene 34, 868–877, doi:10.1038/onc.2014.15 (2015).24608431 [OpenAIRE] [PubMed] [DOI]

14 Qin H, Malek S, Cowell JK & Ren M Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model. Oncogene 35, 5686–5691, doi:10.1038/onc.2016.118 (2016).27065320 [OpenAIRE] [PubMed] [DOI]

15 Forbes SA COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res 45, D777–D783, doi:10.1093/nar/gkw1121 (2017).27899578 [OpenAIRE] [PubMed] [DOI]

44 references, page 1 of 3
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