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. 2025 Apr;132(7):660-669.
doi: 10.1038/s41416-025-02960-3. Epub 2025 Feb 18.

Associations of mucinous differentiation and mucin expression with immune cell infiltration and prognosis in colorectal adenocarcinoma

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

Associations of mucinous differentiation and mucin expression with immune cell infiltration and prognosis in colorectal adenocarcinoma

Hanna Elomaa et al. Br J Cancer. 2025 Apr.

Abstract

Background: The production of extracellular mucus and expression of mucins are commonly aberrant in colorectal cancer, yet their roles in tumour progression remain unclear.

Methods: To investigate the potential influence of mucus on immune response and prognosis, we analysed mucinous differentiation (non-mucinous, 0%; mucinous component, 1-50%; mucinous, >50%) and its associations with immune cell densities (determined with three multiplex immunohistochemistry assays or conventional immunohistochemistry) and survival in 1049 colorectal cancer patients and a validation cohort of 771 patients. We also assessed expression patterns of transmembrane (MUC1, MUC4) and secreted (MUC2, MUC5AC and MUC6) mucins using immunohistochemistry.

Results: Mucinous differentiation was associated with higher densities of CD14+HLADR- immature monocytic cells and M2-like macrophages in mismatch repair (MMR) proficient tumours, and lower T-cell densities in MMR-deficient tumours. Mucinous differentiation was not associated with cancer-specific survival in multivariable Cox regression models. Higher cytoplasmic MUC1 expression independently predicted worse cancer-specific survival (multivariable HR for high vs. negative to low expression, 2.14; 95% CI: 1.26-3.64). It was also associated with increased myeloid cell infiltration in MMR-proficient tumours.

Conclusions: Although mucinous differentiation did not independently predict survival, extracellular mucus and MUC1 expression could promote tumour progression through immunosuppression.

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Conflict of interest statement

Competing interests: TT Seppälä reports consultation fees from Mehiläinen, Tillots Pharma 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 remaining authors declare no competing interests. Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki. The main cohort was approved by the Regional Medical Research Ethics Committee of the Wellbeing services county of Central Finland (Dnro13U/2011, 1/2016, 8/2020, and 2/2023), the Finnish Medicines Agency (Fimea), and the Central Finland Biobank (BB23-0172). The need to obtain informed consent from the study patients was waived (Dnro FIMEA/2023/001573, 4/2023). The validation cohort was approved by the Regional medical research ethics committee of the Wellbeing services county of North Ostrobothnia (25/2002, 42/2005, 122/2009, 37/2020), Fimea (FIMEA/2022/001941), and Biobank Borealis (BB-2017_1012). Patients gave written informed consent for the study.

Figures

Fig. 1
Fig. 1. Mucinous differentiation in colorectal cancer.
Examples of a non-mucinous tumour, a tumour with a mucinous component, and a mucinous tumour.
Fig. 2
Fig. 2. Immune cell phenotyping and associations between mucinous differentiation and immune cell densities.
a pseudo-immunofluorescence images for visualising three multiplex immunohistochemistry staining panels. b Cell phenotyping maps for immune cell subtypes, tumour cells, and other cells. c Associations between mucinous differentiation and immune cell densities in MMR-proficient and deficient tumours. P values were determined using the Wilcoxon rank-sum test. Statistically significant correlations are shown with asterisks (***P < 0.0001; **P < 0.001; *P < 0.005). Immune cell density analyses for MMR-proficient and deficient tumours are based on 870 and 156 cases (T cells, macrophages, M1-like macrophages, M2-like macrophages), 873 and 159 cases (B cells, plasma cells), 856 and 152 cases (mature monocytic cells, immature monocytic cells, granulocytes, mast cells), respectively. MMR, mismatch repair.
Fig. 3
Fig. 3. Kaplan–Meier estimates for cancer-specific survival.
Kaplan–Meier survival curves for mucinous differentiation for all patients, patients with MMR-proficient tumours, and patients with MMR-deficient tumours in a the main cohort and b the validation cohort. MMR mismatch repair.
See this image and copyright information in PMC

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