(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.
Lucantonio et al. (Sat,) studied this question.