Stroma AReactive Invasion Front Areas (SARIFA), tumour immune microenvironment, and survival in colorectal cancer

Background: SARIFA (Stroma AReactive Invasion Front Areas), defined as the direct contact between a tumour cell cluster and adipose cells at the invasion margin, has been proposed as a prognostic marker in gastrointestinal cancers. We hypothesized that SARIFA is associated with an immunosuppressive tumour microenvironment. Methods: SARIFA status was evaluated in two large colorectal cancer cohorts (N = 1876). Survival analyses were performed using multivariable Cox regression. Immune cell densities were analysed utilizing multiplex and conventional immunohistochemistry combined with digital image analysis. Results: SARIFA-positivity was independently associated with a shorter cancer-specific survival in both cohorts [Cohort 1: hazard ratio (HR) for SARIFA-positive (vs. negative) 1.75 (95% CI 1.35–2.25), P < 0.0001; Cohort 2: HR for SARIFA-positive (vs. negative) 2.09 (95% CI 1.43–3.05), P = 0.0001]. SARIFA-positivity was associated with lower densities of CD3⁺ T cells, CD66b⁺ granulocytes, M1-like macrophages, and CD14⁺HLA-DR⁺ mature monocytic cells, but higher densities of M2-like macrophages and CD14⁺HLA-DR^- immature monocytic cells. Mean Cohen’s kappa for SARIFA evaluation between eight investigators was 0.80. Conclusions: SARIFA status is a highly reproducible, independent prognostic factor in colorectal cancer. SARIFA-positivity is associated with lower densities of antitumourigenic immune cells and the polarisation of macrophages towards a protumourigenic M2-like phenotype.