2025

Tapiainen, Vilja V.; Sirniö, Päivi; Elomaa, Hanna; Karjalainen, Henna; Äijälä, Ville K.; Kastinen, Meeri; Kehusmaa, Akseli; Pohjanen, Vesa-Matti; Lindgren, Outi; Sirkiä, Onni; Ahtiainen, Maarit; Helminen, Olli; Wirta, Erkki-Ville; Rintala, Jukka; Saarnio, Juha; Rautio, Tero; Seppälä, Toni T.; Böhm, Jan; Mecklin, Jukka-Pekka; Tuomisto, Anne; Mäkinen, Markus J.; Väyrynen, Juha P.

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.