Colon cancerAn immunological approach

Resumen

Cellular fusion exists as a physiological mechanism which is involved in essential processes such as fertilisation and osteoclasts formation. However, every physiological pathway can become pathological if aberrant. In this regard, cancer cell fusion has emerged as an alternative mechanism that aims to explain most of the poorly understood hallmarks of cancer. In this work, we have evaluated the cell fusion between a colon cancer stem cell and human monocyte, together with the characterisation of the resulting tumour hybrid cells (THCs). THCs resulted after a 5-day in vitro co-culture between colon cancer stem cells and human monocytes, and these were identified as CD45+CD14+EpCAM+. Functional assays showed enhanced migratory and proliferation abilities of these THCs when compared to their parental cells. Moreover, when sorted THCs, EpCAM+ colon cancer stem cells and CD14+ human monocytes were co-cultured with human peripheral blood mononuclear cells (PBMCs), proliferation of T lymphocytes was lower in the presence of THCs, supporting their immune evasion abilities. Not only that, when a blocking antibody against SIGLEC5 was used, CD4 T cell proliferation was recovered, showing the involvement of SIGLEC5 in the immune evasion mechanisms of THCs. Moving on to patients, THCs were identified in circulation and tumour tissue samples of colon cancer patients with the same CD45+CD14+EpCAM+ signature. Next, an array of soluble immune-checkpoints (ICs) were characterised in the plasma samples of our colon cancer patient cohort. Within these, levels of soluble SIGLEC5 (sSIGLEC5) were found to be significantly higher in patients compared to healthy volunteers (HVs). Furthermore, concentration of sSIGLEC5 was found significantly higher in exitus patients. Following a logistic regression model including 22 variables, sSIGLEC5 was found to be an independent survival marker in colon cancer patients. Finally, in an attempt to study the origin of sSIGLEC5, and because of its already described involvement in the innate immune system, SIGLEC5 expression was found to be significantly higher in the membrane of circulating monocytes and neutrophils of colon cancer patients compared to HVs. Altogether, these data support a novel role of SIGLEC5 as an immune evasion mechanism for THCs and as potent exitus predictor in colon cancer patients. These results open new paths towards the identification of novel biomarkers which could aid in patient stratification.