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Clinical Studies

Prognostic role of tumour-infiltrating lymphocytes and macrophages in relation to MSI, CDX2 and BRAF status: a population-based study of metastatic colorectal cancer patients

British Journal of Cancer volume 126, pages 48–56 (2022)Cite this article

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Abstract

Background

Tumour-infiltrating CD3, CD8 lymphocytes and CD68 macrophages are associated with favourable prognosis in localised colorectal cancer, but the effect in metastatic colorectal cancer (mCRC) is not established.

Methods

A Scandinavian population-based cohort of non-resectable mCRC patients was studied. Tissue microarrays (n = 460) were stained with CD3, CD8 and CD68 using fluorescence-based multiplex immunohistochemistry. Associations with clinicopathological variables, overall survival (OS) and progression-free survival were estimated.

Results

Two-thirds of microsatellite instable (MSI) and one-fourth of microsatellite stable (MSS) tumours displayed the highest quartile density of CD8. For CD3 high vs low cases, median OS was 20 vs 16 months (HR: 0.76, 95% CI: 0.59, 0.76, p = 0.025) with 3-year OS of 27 vs 13%. For CD68 high vs low cases, median OS was 23 vs 15 months (HR: 0.69, 95% CI: 0.54, 0.88, p = 0.003) with 3-year OS of 28 vs 12%. MSI, BRAF mutation and CDX2 loss were negative prognostic markers independent of tumour immune infiltration.

Conclusions

In mCRC, high lymphocyte infiltration was found in proportions of MSI and MSS tumours—potential subgroups of immunotherapy response. Tumour-infiltrating CD3 lymphocytes and CD68 macrophages were associated with median and long-term survival. MSI was a significant negative prognostic marker despite high immunogenicity.

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Fig. 1: Fluorescence-based immunohistochemistry staining on tumour tissue microarrays with a multimarker panel of CD3 and CD8 lymphocytes and CD68 macrophages in a Scandinavian population-based cohort of metastatic colorectal cancer.
Fig. 2: Density of tumour-infiltrating CD3, CD8 lymphocytes and CD68 macrophages according to tumour microsatellite instability (MSI) and microsatellite stable (MSS) status in a Scandinavian population-based cohort of metastatic colorectal cancer.
Fig. 3: Overall survival (OS) according to high (>median) vs low tumour infiltration of CD3 and CD8 lymphocytes and CD68 macrophages in a Scandinavian population-based cohort of metastatic colorectal cancer treated with first-line chemotherapy.

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Data availability

Data can be made available upon reasonable request.

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Acknowledgements

We would like to thank Randi Eikeland (Haukeland University Hospital, Bergen, Norway) for data management.

Funding

This study has received grants from Lions Cancer Foundation (Sweden), Selanders Foundation (Sweden), Uppsala University Hospital (Sweden), the Swedish Cancer Society, the Norwegian Cancer Society and the South-Eastern Norway Regional Health Authorities.

Author information

Authors and Affiliations

  1. Department of Clinical Science, University of Bergen, Bergen, Norway

    Kristine Aasebø, Olav Dahl & Halfdan Sorbye

  2. Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    Jarle Bruun, Christian H. Bergsland & Ragnhild A. Lothe

  3. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    Christian H. Bergsland & Ragnhild A. Lothe

  4. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Luís Nunes & Bengt Glimelius

  5. Department of Global Public Health and Primary Care, Lifestyle Epidemiology Group, University of Bergen, Bergen, Norway

    Geir Egil Eide

  6. Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway

    Geir Egil Eide

  7. Department of Oncology, Odense University Hospital, Odense, Denmark

    Per Pfeiffer

  8. Department of Oncology, Haukeland University Hospital, Bergen, Norway

    Olav Dahl & Halfdan Sorbye

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Contributions

HS, PP and BG designed the study and was responsible for patient collection. CHB, JB and RAL were responsible for multiplex IHC analyses and digital image analyses. KA collected and assembled all patient data. LN was responsible for the targeted gene panel DNA sequencing analyses. KA and GEE performed the statistical analyses. KA drafted the manuscript with HS, who supervised the project together with BG, OD and RAL. All authors contributed to manuscript revision and approved the submitted version.

Corresponding author

Correspondence to Kristine Aasebø.

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This study was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients seen at the clinics. The study was approved by the regional ethical committees in Norway (Regional Committee for Medical and Health Research Ethics - REC West), Sweden (Regional Ethical Committee Uppsala) and Denmark (The Regional Scientific Ethical Committees for Southern Denmark).

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Aasebø, K., Bruun, J., Bergsland, C.H. et al. Prognostic role of tumour-infiltrating lymphocytes and macrophages in relation to MSI, CDX2 and BRAF status: a population-based study of metastatic colorectal cancer patients. Br J Cancer 126, 48–56 (2022). https://doi.org/10.1038/s41416-021-01586-5

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