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Background <p>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.</p> Methods <p>SARIFA status was evaluated in two large colorectal cancer cohorts (<i>N</i> = 1876). Survival analyses were performed using multivariable Cox regression. Immune cell densities were analysed utilizing multiplex and conventional immunohistochemistry combined with digital image analysis.</p> Results <p>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), <i>P</i> &lt; 0.0001; Cohort 2: HR for SARIFA-positive (vs. negative) 2.09 (95% CI 1.43–3.05), <i>P</i> = 0.0001]. SARIFA-positivity was associated with lower densities of CD3<sup>+</sup> T cells, CD66b<sup>+</sup> granulocytes, M1-like macrophages, and CD14<sup>+</sup>HLA-DR<sup>+</sup> mature monocytic cells, but higher densities of M2-like macrophages and CD14<sup>+</sup>HLA-DR<sup>-</sup> immature monocytic cells. Mean Cohen’s kappa for SARIFA evaluation between eight investigators was 0.80.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月7日

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  • 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

摘要

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.