Peripheral Blood as the Sole Source of Cancer Neoantigen and Reactive T-cell Discovery
Year: 2026
Type: article
Abstract: 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 nonsynonymous mutations via cell-free DNA whole-exome sequencing and isolate neoantigen-specific CD4+ and CD8+ T cells based on PD-1 and CD39 coexpression. 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 patients with metastatic cancer. 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 patients with metastatic cancer 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. Significance: This study establishes a blood-based strategy for identifying neoantigens and reactive T cells. By integrating ctDNA exome sequencing with phenotypic selection of circulating T cells, it captures tumor heterogeneity and the systemic antitumor T-cell response, enabling personalized immunotherapy development without tumor biopsies, expanding the accessibility of neoantigen-targeted treatments.
Source: Cancer Discovery
Authors: Andrea Garcia-Garijo, Immaculada Creus-González, Pierre L. Levy, Ana Belén Moreno-Cárdenas, Endika Prieto-Fernández, Maria Lozano-Rabella, Carlos Alberto Fajardo, Ricardo Pujol-Borrell, Albert Marín-Bayó, Johanna Kusnick, Jonatan Gonzalez, Carla Brujas, Jared J. Gartner, Anna Yuste-Estevanez, Alma M. Calahorro, Aya Louhamane, Jose Fernandez, Rebeca Sanz-Pamplona, Thomas B.K. Watkins, Vladimir Galvao, Eva Muñoz-Couselo, Javier Ros, Elena Élez, Mafalda Oliveira, Cristina Saura Manich, Irene Braña, Ana Oaknin, Ramon Alemany, Josep Tabernero, Raquel Perez-Lopez, Simon Turcotte, Alexander M. Frankell, Elena Garralda, Rodrigo A. Toledo, Alena Gros
Institutions: Vall d'Hebron Hospital Universitari, Vall d'Hebron Institute of Oncology, Institut d'Investigació Sanitària Acreditat Institut de Recerca - Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, National Institutes of Health, National Cancer Institute, Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo, Hospital Clínico Universitario Lozano Blesa, Stanford Medicine, Stanford University, Institut d'Investigació Biomédica de Bellvitge, Institut Català d'Oncologia, Centre Hospitalier de l’Université de Montréal, University of Cambridge
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7214735871