Abstract
We have shown that ex vivo pre-conditioning of bone marrow-derived dendritic cells (DC) with low molecular weight hyaluronan (LMW HA) induces antitumor immunity against colorectal carcinoma (CRC) in mice. In the present study we investigated the effects of LMW HA priming on human-tumor-pulsed monocytes-derived dendritic cells (DC/TL) obtained from healthy donors and patients with CRC. LMW HA treatment resulted in an improved maturation state of DC/TL and an enhanced mixed leucocyte reaction activity in vivo. Importantly, pre-conditioning of DC/TL with LMW HA increased their ability to migrate and reduced their attraction to human tumor derived supernatants. These effects were associated with increased CCR7 expression levels in DC. Indeed, a significant increase in migratory response toward CCL21 was observed in LMW HA primed tumor-pulsed monocyte-derived dendritic cells (DC/TL/LMW HA) when compared to LWM HA untreated cells (DC/TL). Moreover, LMW HA priming modulated other mechanisms implicated in DC migration toward lymph nodes such as the metalloproteinase activity. Furthermore, it also resulted in a significant reduction in DC migratory capacity toward tumor supernatant and IL8 in vitro. Consistently, LMW HA dramatically enhanced in vivo DC recruitment to tumor-regional lymph nodes and reduced DC migration toward tumor tissue. This study shows that LMW HA –a poorly immunogenic molecule- represents a promising candidate to improve human DC maturation protocols in the context of DC-based vaccines development, due to its ability to enhance their immunogenic properties as well as their migratory capacity toward lymph nodes instead of tumors.
Highlights
Colorectal carcinoma (CRC) is a one of the leading causes of cancer-related death worldwide
We have previously demonstrated both in vivo and in vitro that Dendritic cells (DC) pre-conditioning with low molecular weight hyaluronan (LMW Hyaluronic acid (HA)) is able to enhance DC migration toward regional lymph nodes in mice [10]
Our previous results showed that pre-incubation of DC with LMW HA was able to induce an efficient antitumoral effect in a CRC mouse model which was found to be mediated by the stimulation of DC maturation and activation, as well as by the induction of a potent migratory capacity towards lymphoid areas in vitro and in vivo [11]
Summary
Colorectal carcinoma (CRC) is a one of the leading causes of cancer-related death worldwide. New therapeutic strategies are needed for advanced CRC patients and those based on mounting immune responses against tumors might play a key role [2,3]. Dendritic cells (DC) are professional antigen presenting cells that have the capacity to generate innate and adaptive immune responses, and are essential to induce immunity against cancer [4]. DC migrate from peripheral blood to different organs and tissues wherein they capture antigens and process them to form MHC-IIpeptide complexes. This non-activated (immature) DC can present self-antigens to T cells, which leads to immune tolerance either through T cell deletion or through the differentiation of regulatory or suppressor T cells [5]. The use of mature DC to prime responses to tumor associated antigens (TAA) provides a promising approach for cancer immunotherapy, but clinically relevant responses have been rather poor until now [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
