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Disease Models, Animal / Immune Checkpoint Inhibitors / Colorectal Neoplasms · Journal article
Oncoimmunology · May 16, 2026
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This preclinical study establishes an orthotopic AKPS (quadruple mutant) organoid-derived colorectal cancer mouse model that recapitulates CD8+ T cell exhaustion phenotypes and responds to anti-PD-1 immunotherapy. The model distinguishes itself from subcutaneous implants by showing greater CD8+ T cell dysfunction and ICI responsiveness, providing a platform for mechanistic investigation of early T cell exhaustion in CRC; however, clinical translation remains unproven.
Preclinical syngeneic orthotopic organoid transplant model with transcriptomic and functional immunological analysis. Immunocompetent mice receiving orthotopic rectal submucosal transplantation of AKPS (quadruple mutant Apc−/− Kras G12D/+ Trp53 R172H/− Smad4−/−) intestinal organoids. Intervention: Anti-PD-1 treatment and CD8+ T cell depletion in orthotopic AKPS tumors. Compared with: Subcutaneous AKPS implants; untreated orthotopic controls implied but not explicitly detailed. Sapienza University of Rome and affiliated Italian institutions.
CD8+ T cells are the predominant leukocyte population in orthotopic AKPS tumors and comprise populations transitioning toward dysfunction CD8+ T cell depletion increased tumor burden in orthotopic AKPS implants, demonstrating their antitumor activity Anti-PD-1 treatment increased dysfunctional CD8+ T cell populations and reduced tumor growth in AKPS orthotopic tumors
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This preclinical tool may enable dissection of early CD8+ T cell exhaustion mechanisms in CRC and screening of novel immunotherapies. However, findings are mouse-based and require validation in human CRC tissue or clinical cohorts before informing patient treatment strategies.
Preclinical organoid-based mouse model study demonstrating proof-of-concept for CD8+ T cell dysfunction characterization and ICI responsiveness, lacking direct clinical validation or comparative efficacy trials.
As stated by the source record.
This preclinical tool may enable dissection of early CD8+ T cell exhaustion mechanisms in CRC and screening of novel immunotherapies. However, findings are mouse-based and require validation in human CRC tissue or clinical cohorts before informing patient treatment strategies.
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Colorectal cancer (CRC) treatment represents a major clinical challenge, with immunotherapy providing durable responses only 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. Preclinical models that faithfully reproduce the immune landscape of human CRC are therefore critical to address these challenges. 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 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.
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