Low expression of Granzyme B in colorectal cancer is associated with signs of early metastastic invasion

Salama P, Phillips M, Platell C & Iacopetta B
(2011) Histopathology 59 , 207–215 Low expression of Granzyme B in colorectal cancer is associated with signs of early metastastic invasion Aims: Tumour‐infiltrating forkhead box P3 (FoxP3⁺) regulatory T cells (T_regs) have stronger prognostic significance than cytotoxic CD8⁺ T cells in colorectal cancer (CRC). Because there is evidence that some tumour‐infiltrating CD8⁺ T cells may be inactive, the present study aimed to investigate the prognostic significance of Granzyme B, one of the major effector molecules of T cells. Methods and results: A tissue microarray containing 963 CRCs was stained immunohistochemically for Granzyme B and the level of expression quantified by digital image analysis. Granzyme B expression was higher in tumours with microsatellite instability (P < 0.0001), a dense lymphocytic infiltrate (P < 0.0001) and location in the proximal colon (P = 0.009), but lower in tumours with vascular invasion (P = 0.007), perineural invasion (P =0.041) and positive nodal status (P < 0.001). Elevated expression of Granzyme B was associated with improved survival on univariate analysis (hazard ratio = 0.65; 95% confidence interval 0.51–0.84; P = 0.001), but not in a multivariate model that included stage, vascular invasion and FoxP3⁺ T_reg cell density. Conclusions: Low expression of Granzyme B was associated with early signs of metastasis in CRC. The stronger prognostic significance of FoxP3⁺ T_regs is in keeping with animal models that suggest these cells act as gatekeepers for the release of Granzyme B from CD8⁺ T cells.