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. 2025 May;132(9):805-813.
doi: 10.1038/s41416-025-02972-z. Epub 2025 Mar 7.

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

Vilja V Tapiainen  1 , Päivi Sirniö  1 , Hanna Elomaa  2   3 , Henna Karjalainen  1 , Ville K Äijälä  1 , Meeri Kastinen  1 , Akseli Kehusmaa  1 , Vesa-Matti Pohjanen  1 , Outi Lindgren  1 , Onni Sirkiä  4   5 , Maarit Ahtiainen  6 , Olli Helminen  1 , Erkki-Ville Wirta  7   8 , Jukka Rintala  1 , Juha Saarnio  1 , Tero Rautio  1 , Toni T Seppälä  8   9   10 , Jan Böhm  4 , Jukka-Pekka Mecklin  3   11 , Anne Tuomisto  1 , Markus J Mäkinen  1 , Juha P Väyrynen  12
Affiliations

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

Vilja V Tapiainen et al. Br J Cancer. 2025 May.

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.

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Conflict of interest statement

Competing interests: TTS reports consultation fees from Tillots Pharma, Mehiläinen and Nouscom, being a co-owner and CEO of Healthfund Finland Ltd, and a position in the Clinical Advisory Board and as a minor shareholder of Lynsight Ltd. The other authors declare that they have no conflicts of interest. Ethical approval: The study was conducted in accordance with the Declaration of Helsinki. For Cohort 1, the study was conducted under approval from the Regional medical research ethics committee of the Wellbeing services county of Central Finland (Dnro 13U/2011, 1/2016, 8/2020, 2/2023), Central Finland Biobank (BB23-0172), and Fimea (Dnro FIMEA/2023/001573, 4/2023). For Cohort 2, the study was conducted under approval from the Regional medical research ethics committee of the Wellbeing services county of North Ostrobothnia (25/2002, 42/2005, 122/2009, 37/2020), Biobank Borealis (BB-2017_1012) and Fimea (FIMEA/2022/001941). In Cohort 2, all participants gave written informed consent for the study. For Cohort 1, The need to obtain informed consent from the study patients was waived (Dnro FIMEA/2023/001573, 4/2023).

Figures

Fig. 1
Fig. 1. Evaluation of Stroma AReactive Invasion Front Areas (SARIFA) status in colorectal cancer.
a A representative example of a SARIFA-positive case. b A representative example of a SARIFA-negative case. Scale bars are 250 µm. c The reproducibility of SARIFA status evaluation between eight investigators, measured with Cohen’s kappa. R researcher, P pathologist
Fig. 2
Fig. 2. Stroma AReactive Invasion Front Areas (SARIFA) status and survival in colorectal cancer.
Kaplan–Meier curves for cancer specific survival in cohort 1 (a, b) and in cohort 2 (c, d). All patients (a, b) and the pT3/4 patient subgroup (b, d) were analysed.
Fig. 3
Fig. 3. Multiplex immunohistochemistry panel, image analyses and immune cell densities.
Example images of multiplex immunohistochemistry for detecting B cells (a), macrophages (b) and myeloid cells (c). Scale bars are 100 µm. Digital image analysis was utilized to create corresponding cell maps (d–f). Boxplot of immune cell densities (g) according to SARIFA status in colorectal cancer. Analyses were based on cohort 1 immune cell data, in which N = 1065 for CD3+ T cells, macrophages, M1-like macrophages, and M2-like macrophages; N = 1070 for CD20+CD79A+ B cells and CD20-CD79A+ plasma cells; N = 1045 for CD14+ monocytic cells, CD14+HLA-DR+ mature monocytic cells, CD14+HLA-DR- immature monocytic cells, CD66B+ granulocytes, and tryptase+ mast cells. ns: p > 0.05, *p < 0.05, **p < 0.01, ***p < 0.001. ****p < 0.0001.
See this image and copyright information in PMC

References

    1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63. - PubMed
    1. Arneth B. Tumor Microenvironment. Medicina. 2019;56:15. - PMC - PubMed
    1. LeBleu VS. Imaging the Tumor Microenvironment. Cancer J. 2015;21:174–8. - PMC - PubMed
    1. Turley SJ, Cremasco V, Astarita JL. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol. 2015;15:669–82. - PubMed
    1. Brierley J, Gospodarowicz MK, Wittekind CH (eds). TNM classification of malignant tumours, 8th edn. (John Wiley & Sons, Inc., Oxford, UK, 2017).

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