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An orthotopic organoid-based model to track CD8⁺ T cell exhaustion dynamics in colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) treatment represents a major clinical challenge, with immunotherapy providing durable responses in a minority of patients. A deeper understanding of CD8⁺ T cell exhaustion and its contribution to immune checkpoint inhibitor (ICI) responsiveness is essential for the development of more effective therapeutic strategies. Here, we established a syngeneic organoid-based orthotopic CRC mouse model by transplanting quadruple mutant Apc⁻/⁻KrasG12D/+Trp53R172H/⁻Smad4⁻/⁻ (AKPS) intestinal organoids into the rectal submucosa of immunocompetent mice. Single-cell transcriptomic profiling revealed that tumor-infiltrating CD8⁺ T cell phenotypes span a continuum of differentiation states, ranging from precursor exhausted (Tpex) to terminally exhausted (Tex) CD8+ cell subsets. In contrast, subcutaneous implants of AKPS were infiltrated by mixed CD4⁺ and CD8⁺ cell subsets, with CD8⁺ T cells exhibiting a markedly lower exhaustion profile, highlighting the limitations of heterotopic tumor models for studying antitumor immune responses. Functionally, CD8⁺ T cell depletion led to increased tumor burden in orthotopic AKPS implants, underscoring their antitumor activity. Importantly, anti-PD-1 treatment reduced tumor growth, demonstrating the responsiveness of this model to ICIs. Together, our findings establish the AKPS orthotopic CRC model as a powerful platform to dissect the molecular mechanisms of CD8⁺ T cell exhaustion and to preclinically evaluate novel immunotherapeutic interventions in CRC.

ORGANISM(S): Mus musculus

PROVIDER: GSE310071 | GEO | 2026/05/27

REPOSITORIES: GEO

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