Stroma AReactive Invasion Front Areas (SARIFA), tumour immune microenvironment, and survival in colorectal cancer
Vilja V. Tapiainen, Päivi Sirniö, Hanna Elomaa, Henna Karjalainen, Ville K. Äijälä, Meeri Kastinen, Akseli Kehusmaa, Vesa‐Matti Pohjanen, Outi Lindgren, Onni Sirkiä, Maarit Ahtiainen, Olli Helminen, Erkki‐Ville Wirta, Jukka Rintala, Juha Saarnio, Tero Rautio, Toni T. Seppälä, Jan Böhm, Jukka‐Pekka Mecklin, Anne Tuomisto, Markus J. Mäkinen, Juha P. Väyrynen
Abstract
Abstract 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.