An orthotopic organoid-based model to study early CD8⁺ T cell dysfunction and immunotherapy response in colorectal cancer
(AKPS) intestinal organoids into the rectal submucosa of immunocompetent mice. Single-cell transcriptomic profiling revealed that CD8⁺ T cells represent the predominant leukocyte population within the tumor infiltrate and comprise populations transitioning toward dysfunction. Functionally, CD8⁺ T cell depletion led to increased tumor burden in orthotopic AKPS implants, underscoring their antitumor activity. Importantly, anti-PD-1 treatment increased the abundance of dysfunctional CD8⁺ T cell populations within AKPS tumors and reduced tumor growth, demonstrating the responsiveness of this model to ICIs. In contrast, subcutaneous implants of AKPS were infiltrated by mixed CD4⁺ and CD8⁺ T cell subsets, with CD8⁺ T cells exhibiting a markedly less dysfunctional profile, highlighting the limitations of heterotopic tumor models for studying antitumor immune responses. Together, our findings establish the AKPS orthotopic CRC model as a platform to dissect the molecular mechanisms of early CD8⁺ T cell dysfunction and to preclinically evaluate novel immunotherapeutic interventions in CRC.
Authors
- Lorenzo Lucantonio (ORCID: https://orcid.org/0000-0003-0554-0658)
- Rosa Molfetta (ORCID: https://orcid.org/0000-0003-2904-6371)
- Cinzia Fionda (ORCID: https://orcid.org/0000-0003-0636-7607)
- Angela Gismondi (ORCID: https://orcid.org/0000-0001-6731-6366)
- Ludovica Schiano (ORCID: https://orcid.org/0000-0003-3866-2555)
- Giovanna Peruzzi (ORCID: https://orcid.org/0000-0002-6517-9107)
- Giuseppe Pietropaolo (ORCID: https://orcid.org/0000-0002-4802-7312)
- Andrea Kosta (ORCID: https://orcid.org/0000-0001-9094-0343)
- Francesca Sozio (ORCID: https://orcid.org/0000-0002-9789-1529)
- Antonio Francesco Campese (ORCID: https://orcid.org/0000-0002-8535-6609)
- Mattia Laffranchi (ORCID: https://orcid.org/0000-0002-0556-6068)
- Giovanni Bernardini (ORCID: https://orcid.org/0000-0002-3705-2598)
- Giuseppe Sciumè
- Stabile Helena
- Silvano Sozzani
- Angela Santoni
Institutions
- Istituto Neurologico Mediterraneo (IT)
- Italian Institute of Technology (IT)
- Bambino Gesù Children's Hospital (IT)
- Center for Nano Science and Technology (IT)
- Istituto Pasteur (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- OncoImmunology
- Published
- 2026-05-16
- DOI
- https://doi.org/10.1080/2162402x.2026.2674362
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Sapienza Università di Roma
- Associazione Italiana per la Ricerca sul Cancro