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Cited by 620Cancer Immunotherapy and BiomarkersCancer Genomics and DiagnosticsImmunotherapy and Immune Responses

Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors

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Miao, Diana, Margolis, Claire A., Vokes, Natalie I., Liu, David, Taylor-Weiner, Amaro, Wankowicz, Stephanie M., Adeegbe, Dennis, Keliher, Daniel +23 more·2018·Nature Genetics
DOI 10.1038/s41588-018-0200-2PMC PMC6119118
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Abstract

Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.

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  • In an independent BLCA cohort of 27 patients treated with PD-1/PD-L1 inhibitors, PathTIGR-predicted response groups were significantly associated with actual clinical outcomes (Fisher's exact test P = 0.03).

    “The predicted response groups showed a statistically significant association with the actual clinical outcomes (Fisher’s exact test, P = 0.03; Fig. 3E).”

    From PathTIGR: A pathway topology-informed graph representation learning framework for immunotherapy response prediction (2026) · cites this paper as [36]

    The Results section on cohort consolidation reports 27 bladder cancer patients in the source paper’s analysis cohort. It does not report PathTIGR-predicted response groups or the claimed Fisher’s exact test result of P = 0.03; its Online Methods describe Fisher’s exact tests for molecular features instead. The source supports the cohort identification, but not the stated association. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Among BLCA patients predicted to respond by PathTIGR, the proportion of true responders was 85.7%.

    “Among the patients predicted to respond, the proportion of true responders reached 85.7%.”

    From PathTIGR: A pathway topology-informed graph representation learning framework for immunotherapy response prediction (2026) · cites this paper as [36]

    The Results discuss genomic features associated with response, and the Online Methods describe response classification and statistical analyses. Searches for PathTIGR, 85.7%, and the proportion of true responders among predicted responders found no passage reporting this result for bladder cancer patients. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Authors
Miao, D., Margolis, C. A., Vokes, N. I., Liu, D., Taylor-Weiner, A., Wankowicz, S. M., Adeegbe, D., Keliher, D., Schilling, B., Tracy, A., Manos, M., Chau, N. G., Hanna, G. J., Polak, P., Rodig, S. J., Signoretti, S., Sholl, L. M., Engelman, J. A., Getz, G., Jänne, P. A., Haddad, R. I., Choueiri, T. K., Barbie, D. A., Haq, R., Awad, M. M., Schadendorf, D., Hodi, F. S., Bellmunt, J., Wong, K.-K., Hammerman, P., & Van Allen, E. M.
Affiliations
  • Broad Institute (US)
  • NYU Langone Health (US)
  • Universitätsklinikum Würzburg (DE)
  • Dana-Farber Cancer Institute (US)
  • Brigham and Women's Hospital (US)
  • Massachusetts General Hospital (US)
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2018-08-27
Volume
50
Issue
9
Pages
1271-1281
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-018-0200-2
PMC
PMC6119118
OpenAlex
W2888546921
Cited by
620
References
17
Citations by year
2026: 21 · 2025: 57 · 2024: 61 · 2023: 99 · 2022: 111 · 2021: 122 · 2020: 92 · 2019: 53 · 2018: 2
FWCI
25.65
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Human Genome Research Institute (T32HG002295)
  • National Cancer Institute (R01CA166480, K08CA188615, R01CA227388, R01CA140594, T32CA009172)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
immune checkpoint blockade, microsatellite stable tumors, tumor mutational burden, predictive biomarkers, driver genes, mutational signatures, antitumor immunity, treatment response, solid tumors
MeSH terms
Humans, Immunity, Mutation, Neoplasms, Cohort Studies, Microsatellite Repeats, Genomics, Exome

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