Defective Generation and Maturation of Dendritic Cells from Monocytes in Colorectal Cancer Patients during the Course of Disease

Abstract

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in Western countries. Today, the role of the host’s immune system in controlling the progression and spread of solid tumors is broadly established. Tumor immunosurveillance escape mechanisms, such as those involving dendritic cells (DCs), the most important antigen-presenting cells, are likewise recognized processes involved in cancer. The present study evaluates the ability of CRC patients to generate DCs in vitro from circulating monocytes at both pre- and post-operative timepoints; the results are correlated with the stage of disease to shed light on the systemic immune statuses of CRC patients. Our data showed that patients’ DCs had lower co-stimulatory molecule expression and were less able to present antigens to allogeneic T cells compared to healthy controls’ (HC) DCs. Furthermore altered cytokine secretion, such as increased IL-10 and reduced IL-12 and TNF-α, was observed. At the post-operative timepoints we observed a recovery of the patients’ ability to generate immature DCs, compared to HCs, but the maturational capacity remained affected. Our study conclusively highlights the persistently impaired in vitro generation of fully mature and functional DCs, which appears to be more altered during advanced stages. This work sheds light on a dendritic cell-based tumor immune escape mechanism that could be useful for the development of more effective immunotherapeutic strategies.

Monocyte-derived dendritic cells from patients with cervical intraepithelial lesions

“…Orsini et al observed that colorectal cancer patients had deficiency in monocyte-derived DCs differentiation, with reduced expression of co-stimulatory molecules and reduced IL-12 and TNF-α synthesis (38). In our study, no significant changes in the expression of the co-stimulatory molecule CD86 were observed, suggesting that the degree of the cervical lesion was not able to interfere on the expression of this molecule.…”

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…The IL-10 was found to be uniquely able to convert fully developed DCs to immature macrophage-like cells in a physiologically highly relevant tumor model in mice [127]. Similarly to this model, patients with colorectal cancer (CRC) are characterized by an increased Tregs-related IL-10 level, while DCs had lower costimulatory molecule expression and were less able to present antigens to allogeneic T cells [128,129]. Although APCs, monocytes, NK cells, T regulatory, and CD8+ lymphocytes are able to exhibit potent antitoxic action against tumor cells, IL-10 mRNA was detected in melanoma-associated macrophages and lymphocytes, suggesting for facilitated evolution of the primary melanoma and rendering of regional lymph nodes susceptible to metastases [118][119][120][121]130].…”

Long-term alterations in monocyte function after elective cardiac surgery

“…An aberrant inflammatory response is a significant cause of morbidity and mortality following a critical insult or surgery . The emergence of a new immunological equilibrium following a critical insult has been proposed as the underlying cause of progressive organ failure, hastened atherosclerosis and resurgence of opportunistic infections . It is uncertain whether postoperative immunological responses to subsequent challenges over an extended period of time are generalisable to all patients .…”

“…Most importantly, they are a source of dendritic cells, which are crucial to the control of the immune response . Loss of monocyte functional plasticity, heralded by a decreased ability of monocytes to become dendritic cells, signifies an abnormal immune response and is linked to unfavourable outcomes after trauma, pneumonia and cardiac surgery . Thus, monocyte plasticity is significant, and pivotal to the immune response and maintenance of homoeostasis.…”