The circulating soluble form of the CD40 costimulatory immune checkpoint receptor and liver metastasis risk in rectal cancer

Sebastian Meltzer, Annette Torgunrud, Hanna Abrahamsson, Arne Mide Solbakken, Kjersti Flatmark, Svein Dueland, Kine Mari Bakke, Paula Anna Bousquet, Anne Negård, Christin Johansen, Lars Gustav Lyckander, Finn Ole Larsen, Jakob Vasehus Schou, Kathrine Røe Redalen, Anne Hansen Ree, Sebastian Meltzer, Annette Torgunrud, Hanna Abrahamsson, Arne Mide Solbakken, Kjersti Flatmark, Svein Dueland, Kine Mari Bakke, Paula Anna Bousquet, Anne Negård, Christin Johansen, Lars Gustav Lyckander, Finn Ole Larsen, Jakob Vasehus Schou, Kathrine Røe Redalen, Anne Hansen Ree

Abstract

Background: In colorectal cancer, the inflamed tumour microenvironment with its angiogenic activities is immune- tolerant and incites progression to liver metastasis. We hypothesised that angiogenic and inflammatory factors in serum samples from patients with non-metastatic rectal cancer could inform on liver metastasis risk.

Methods: We measured 84 angiogenic and inflammatory markers in serum sampled at the time of diagnosis within the population-based cohort of 122 stage I-III patients. In a stepwise manner, the statistically strongest proteins associated with time to development of liver metastasis were analysed in the corresponding serum samples from 273 stage II-III rectal cancer patients in three independent cohorts.

Results: We identified the soluble form of the costimulatory immune checkpoint receptor cluster of differentiation molecule 40 (sCD40) as a marker of liver metastasis risk across all patient cohorts-the higher the sCD40 level, the shorter time to liver metastasis. In patients receiving neoadjuvant treatment, the sCD40 value remained an independent variable associated with progression to liver metastasis along with the local treatment response. Of note, serum sCD40 was not associated with progression to lung metastasis.

Conclusions: Circulating sCD40 is a marker of liver metastasis risk in rectal cancer and may be developed for use in clinical practice.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1. sCD40 serum leves in the…
Fig. 1. sCD40 serum leves in the different cohorts.
Patients’ serum levels of the soluble cluster of differentiation molecule 40 (sCD40, open circles) in the Investigation Cohort (IC) and Validation Cohorts (VC1–3); grey line, the cohort median value.
Fig. 2. High or low sCD40 and…
Fig. 2. High or low sCD40 and risk of liver metastasis development.
Cumulative percentages of cases with liver progression among all patients grouped with higher or lower than the median serum value of the soluble cluster of differentiation molecule 40 (sCD40).

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