Both CD8 + and CD4 + T regulatory cells are associated with poor survival in colorectal cancer

Abstract Previous studies in colorectal cancer have linked high levels of FoxP3 + regulatory T-cells (Treg) (CRC) to favourable prognosis. However, this contradicts the well-established immunosuppressive function of Treg. We resolved this conundrum using multiplex immunohistochemistry to characterise Foxp3⁺and IL-10⁺ Treg in 1,000, consecutively recruited patients’ tumours. Although Foxp3⁺ cells associated with improved outcomes, this effect was confounded by high numbers of CD8 + effector T-cells (Teff). In contrast, a high ratio of CD8⁺ Treg to CD8⁺ Teff cells correlated with poor survival. Although the total CD4⁺ T-cell count was not prognostic, CD4 + Teff were linked to improved outcomes, suggesting that the Treg fraction within the population may mask beneficial immune responses. Spatial proximity (< 12 µm) between CD4⁺ Treg and CD8⁺ Teff cells associated with adverse prognosis highlighting the under-recognised role of CD8⁺ Treg and importance of the spatial dynamics of Treg–Teff interactions in modulating the tumour microenvironment.