Site-specific immune remodeling underlies resistance to dual immune checkpoint blockade in metastatic colorectal cancer
Year: 2026
Type: preprint
Abstract: Immune checkpoint inhibitors (ICIs) have limited efficacy in metastatic colorectal cancer (mCRC) with proficient mismatch repair and microsatellite stability (pMMR/MSS), with liver metastases emerging as a dominant determinant of resistance. Whether this reflects a failure to activate antitumor immunity or a failure to direct it remains unclear. We investigated this in the phase II SERPENTINE trial of dual PD-L1 and CTLA-4 blockade by integrating paired pre-treatment and on-treatment single-cell transcriptomic and T-cell receptor (TCR) profiling (388,196 cells; 95,617 clonotypes) metastatic biopsies with deep TCR sequencing of matched peripheral blood (57,902,418 clonotypes). In MSS mCRC, clinical benefit was restricted to patients without liver metastases, whereas all patients with liver metastases progressed. Dual ICI induced systemic T-cell priming regardless of metastatic site, mobilizing therapy-expanded clones that trafficked to both lung and liver lesions, but the fate of this response was determined locally. In lung metastases, therapy-specific clones focused into tissue-resident, proliferative, tumor-reactive CD8+ T-cell states. In liver metastases, the same activation was dispersed: regulatory T cells and suppressive myeloid populations expanded, TCR repertoires diversified, and exhaustion-associated T-cell gene networks fragmented. Cross-lineage co-expression analysis further revealed that tumor proliferation increased in concert with cytotoxic CD8+ T-cell programs, indicating effector engagement that fails to restrain tumor growth. These findings show that resistance to ICI in liver metastases arises from tissue-specific misdirection of immune activation away from productive antitumor immunity, identifying multicellular coordination of the immune response in the metastatic microenvironment as a determinant of therapeutic efficacy.
Source: medRxiv
Authors: Iosune Baraibar, Samuel Morabito, Gerard Deuner-Cos, Ginevra Caratù, Juan Luis Melero, Miren Berasategi, Marta Soto, Marta Grzelak, Paula Nieto, Davide Maspero, Francesc Salvà, Nadia Saoudi, Javier Ros, Raquel Pérez-López, Alena Gros, Guillermo Villacampa, Nuria Roson, Javier Carmona, Ariadna García, Arthur Lambert, Nadia Martinez-Martin, Patricia Casbas-Hernandez, Jorge Zeron-Medina, Josep Tabernero, Asaf Rotem, Juan C. Nieto, Elena Élez, Holger Heyn
Institutions: Vall d'Hebron Hospital Universitari, Vall d'Hebron Institute of Oncology, Centro Nacional de Análisis Genómico, Universitat de Barcelona, Universitat Pompeu Fabra, AstraZeneca (United States), AstraZeneca (Spain), Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Cáncer, Universitat Autònoma de Barcelona, Institució Catalana de Recerca i Estudis Avançats
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: AstraZeneca, Fundación BBVA, Fundació la Marató de TV3, “la Caixa” Foundation, Ministerio de Ciencia, Innovación y Universidades, Mark Foundation For Cancer Research, European Commission, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, European Society for Medical Oncology, Fundación Fero, Horizon 2020 Framework Programme, HORIZON EUROPE Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III
Awards: G1272900390, DECISION ON OPTIMAL COMBINATORIAL THERAPIES IN IMIDS USING SYSTEMS APPROACHES, G1669149419, G3480202686, G4042981725, G4686625910, G4688950647, G5131721712, Identificación de antígenos tumorales no canónicos y análisis de su relevancia en la inmunoterapia del cáncer: inmunogenicidad, valor predictivo y potencial terapeútico, G5805502524, G6731524417, G683246478, G717256432, G7212357086, G745419941, G7455307701, G7683116406, G774329465, G7805098552, G8720657221, G8727914364
OpenAlex ID: W7223271994