Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
Open accessAbstract
The cellular ancestry of tumor antigens: One contributing factor in antitumor immunity is the repertoire of neoantigens created by genetic mutations within tumor cells. Like the corresponding mutations, these neoantigens show intratumoral heterogeneity. Some are present in all tumor cells (clonal), and others are present in only a fraction of cells (subclonal). In a study of lung cancer and melanoma, McGranahan et al. found that a high burden of clonal tumor neoantigens correlated with improved patient survival, an increased presence of tumor-infiltrating lymphocytes, and a durable response to immunotherapy. Science , this issue p. 1463
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Neoantigen landscape and composition is a stronger indicator of response to treatment in melanoma and NSCLC than TMB.
“it has been demonstrated that the landscape and composition of neoantigens within tumors is a stronger indicator of response to treatment in melanoma and NSCLC patients (McGranahan et al., 2016).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as McGranahan et al., 2016
Previous studies have demonstrated subclonal mutations as a marker of response to immune checkpoint inhibition and response to traditional chemotherapy.
“Previous studies have demonstrated subclonal mutations as a marker of response to immune checkpoint inhibition 1548 50 as well as response to traditional chemotherapy.”
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- Authors
- McGranahan, N., Furness, A. J. S., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S. K., Jamal-Hanjani, M., Wilson, G. A., Birkbak, N. J., Hiley, C. T., Watkins, T. B. K., Shafi, S., Murugaesu, N., Mitter, R., Akarca, A. U., Linares, J., Marafioti, T., Henry, J. Y., Van Allen, E. M., Miao, D., Schilling, B., Schadendorf, D., Garraway, L. A., Makarov, V., Rizvi, N. A., Snyder, A., Hellmann, M. D., Merghoub, T., Wolchok, J. D., Shukla, S. A., Wu, C. J., Peggs, K. S., Chan, T. A., Hadrup, S. R., Quezada, S. A., & Swanton, C.
- Affiliations
- The Francis Crick Institute (GB)
- Cancer Research UK (GB)
- Technical University of Denmark (DK)
- Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK.
- University College London (GB)
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
- Broad Institute (US)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Memorial Sloan Kettering Cancer Center (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- McGranahan, Nicholas
- Furness, Andrew J. S.
- Rosenthal, Rachel
- Quezada, Sergio A.
- Swanton, Charles
- ORCID
- McGranahan, Nicholas
- Furness, Andrew J. S.
- Rosenthal, Rachel
- Ramskov, Sofie
- Lyngaa, Rikke
- Saini, Sunil Kumar
- Wilson, Gareth A.
- Birkbak, Nicolai J.
- Hiley, Crispin T.
- Watkins, Thomas B. K.
- Murugaesu, Nirupa
- Mitter, Richard
- Akarca, Ayse U.
- Marafioti, Teresa
- Henry, Jake Y.
- Miao, Diana
- Schilling, Bastian
- Schadendorf, Dirk
- Garraway, Levi A.
- Makarov, Vladimir
- Rizvi, Naiyer A.
- Snyder, Alexandra
- Hellmann, Matthew D.
- Merghoub, Taha
- Wolchok, Jedd D.
- Shukla, Sachet A.
- Wu, Catherine J.
- Peggs, Karl S.
- Chan, Timothy A.
- Hadrup, Sine R.
- Quezada, Sergio A.
- Swanton, Charles
- Venue
- Science
- Published
- 2016-03-25
- Volume
- 351
- Issue
- 6280
- Pages
- 1463-1469
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4984254
- OpenAlex
- W2291298003
- Semantic Scholar
- 573646106a647e2f4b18ca3e430401ac86f8097c
- Cited by
- 3,065
- References
- 38
- Citations by year
- 2026: 163 · 2025: 192 · 2024: 257 · 2023: 270 · 2022: 312 · 2021: 412 · 2020: 372 · 2019: 366 · 2018: 298 · 2017: 278 · 2016: 141 · 2015: 1 · 2014: 1
- FWCI
- 194.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, other-oa)
- Funders
- Cancer Research UK (CRUK)
- Rosetrees Trust
- NovoNordisk Foundation
- Prostate Cancer Foundation
- Breast Cancer Research Foundation
- European Research Council
- EU FP7
- Sam Keen Foundation
- Leukemia and Lymphoma Society
- Blavatnik Family Foundation
- NIH/National Heart, Lung, and Blood Institute (1R01CA155010-02)
- NIH/National Cancer Institute (1R01CA182461-01, 1R01CA184922-01)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- intratumoral heterogeneity, immune checkpoint blockade, anti-PD-1 therapy, CTLA-4 blockade, CD8+ T cells, tumor-infiltrating lymphocytes, lung adenocarcinoma, non-small cell lung cancer, melanoma, mutational burden, antitumor immunity, overall survival, immune checkpoint inhibitor response
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Aged, Aged, 80 and over, Antigens, Neoplasm, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Immunologic Surveillance, Lung Neoplasms, Male, Melanoma, Middle Aged, Mutation, Skin Neoplasms, CD4-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Cell Cycle Checkpoints, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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