Peripheral Blood as the Sole Source for Cancer Neoantigen and Reactive T-Cell Discovery
Neoantigen-targeted T-cell therapies require invasive tumor biopsies to identify neoantigens and reactive T cells, limiting their applicability and potentially underestimating tumor heterogeneity. We propose a novel strategy relying solely on peripheral blood to identify non-synonymous mutations via cell-free DNA whole-exome sequencing and isolate neoantigen-specific CD4+ and CD8+ T cells based on PD-1 and CD39 co-expression. Our method identified most neoantigens and increased the number of T-cell reactivities detected by standard biopsy-based techniques in an initial cohort of eight metastatic cancer patients. Critically, our approach uncovered additional neoantigens missed by tumor biopsy analysis, highlighting the potential for broader neoantigen targeting using liquid biopsies. Analysis of a cohort of 69 metastatic cancer patients revealed that approximately half could be eligible for our blood-only approach. This proof-of-concept study demonstrates the potential of using blood as a surrogate or complement for tumor biopsies to develop neoantigen-reactive T-cell therapies against a broader spectrum of neoantigens.
Authors
- Jared J. Gartner (ORCID: https://orcid.org/0000-0003-2924-3519)
- Alena Gros (ORCID: https://orcid.org/0000-0002-1207-1880)
- Maria Lozano-Rabella (ORCID: https://orcid.org/0000-0002-6304-3919)
- Carlos Alberto Fajardo (ORCID: https://orcid.org/0000-0003-4635-2645)
- Andrea García-Garijo (ORCID: https://orcid.org/0000-0002-7775-0737)
- Simon Turcotte (ORCID: https://orcid.org/0000-0002-0978-736X)
- Endika Prieto‐Fernández (ORCID: https://orcid.org/0000-0001-8378-1495)
- Josep M. Tabernero (ORCID: https://orcid.org/0000-0002-2495-8139)
- Carla Brujas
- Raquel Pérez-López (ORCID: https://orcid.org/0000-0002-9176-0130)
- Élena Elez (ORCID: https://orcid.org/0000-0002-4653-6324)
- Alexander M. Frankell (ORCID: https://orcid.org/0000-0002-0341-7878)
- Vladimir Galvao (ORCID: https://orcid.org/0009-0007-8139-8215)
- Ana Belén Moreno-Cárdenas (ORCID: https://orcid.org/0000-0001-7743-3873)
- Rodrigo Almeida Toledo (ORCID: https://orcid.org/0000-0003-3070-6795)
- Thomas B.K. Watkins (ORCID: https://orcid.org/0000-0001-7414-737X)
- Johanna Kusnick (ORCID: https://orcid.org/0000-0002-4270-6998)
- Mafalda Oliveira (ORCID: https://orcid.org/0000-0001-9152-8799)
- Eva Muñoz‐Couselo (ORCID: https://orcid.org/0000-0001-7556-7608)
- Elena Garralda (ORCID: https://orcid.org/0000-0002-4412-7842)
- Rebeca Sanz‐Pamplona (ORCID: https://orcid.org/0000-0002-2187-3527)
- Jonatan Gonzalez
- Ricardo Pujol‐Borrell (ORCID: https://orcid.org/0000-0001-7833-675X)
- Ana Oaknin (ORCID: https://orcid.org/0000-0002-3592-7194)
- Anna Yuste-Estevanez (ORCID: https://orcid.org/0000-0001-7962-8893)
- Pierre L. Levy (ORCID: https://orcid.org/0000-0003-3213-0080)
- Javier Ros (ORCID: https://orcid.org/0000-0002-8137-5415)
- Irene Braña (ORCID: https://orcid.org/0000-0002-1068-9601)
- Cristina Saura (ORCID: https://orcid.org/0000-0001-8296-5065)
- Ramón Alemany (ORCID: https://orcid.org/0000-0001-8660-550X)
- José Fernández Navarro (ORCID: https://orcid.org/0000-0002-4035-5258)
- A Marín-Bayo (ORCID: https://orcid.org/0009-0006-6156-2172)
- Aya Louhamane
- Alma Calahorro (ORCID: https://orcid.org/0009-0009-6692-9115)
- Immaculada Creus-González
Institutions
- Hebron University (PS)
- Universitat Autònoma de Barcelona (ES)
- National Institutes of Health (US)
- National Health Research Institutes (TW)
- The Francis Crick Institute (GB)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Instituto de Investigación Sanitaria Aragón (ES)
- Centre Hospitalier de l’Université de Montréal (CA)
- Stanford University (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-09-29
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-1779
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00