Tumour microenvironment of both early- and late-stage colorectal cancer is equally immunosuppressive

Abstract

BackgroundTumour microenvironment (TME) of advanced colorectal cancer (CRC) suppresses dendritic cell (DC) maturation. Here, our aim was to determine how the microenvironment of early-stage tumours influences DCs.Methods:Tumour-conditioned media (TCM) was generated by culturing explant tumour tissue in vitro (n=50). Monocyte-derived DCs (MDDCs) of healthy donors or cancer patients were pretreated with TCM and stimulated with lipopolysaccharide (LPS). DC maturation was assessed by flow cytometry and cytokine production measured by ELISA.Results:TCM from both early- and late-staged tumours abrogated LPS-induction of IL-12p70 secretion, while increasing IL-10. The profile of inflammatory mediators in TCM was similar across stages, and all increased pSTAT3 expression by DCs.CRC patient DCs (n=31) secreted low levels of IL-12p70 and failed to upregulate expression of maturation markers in response to LPS. Furthermore, in vitro culture of autologous DCs with TCM did not change the hypo-responsiveness of patient DCs.Conclusion:Our data demonstrates that the TME of all stages of CRC contains inflammatory mediators capable of suppressing local DCs. MDDCs obtained from CRC patients are hyporesponsive to stimuli such as LPS. Measures to reverse the negative influence of the TME on DCs will optimise cancer vaccines in both early- and late-stage CRC.

Obesity, Inflammation, and Cancer

“…The CRC microenvironment contains immunosuppressive cytokines such as TGF-β and IL-10, which limit antitumor T cell responses (136). For prognosis, a high density of CD8 + T cells in the primary lesion is associated with less tumor invasion and improved survival, whereas a high density of Tregs is associated with poorer outcomes (137).…”

“…Tumor-infiltrating Tregs play an important role in preventing an antitumor T cell response, and a unique latency-associated peptide (LAP) + Treg was recently discovered in CRC tumors that secretes more IL-10 and TGF-β and is more immunosuppressive than LAP − Foxp3 + Tregs (138). Dendritic cells, key players in orchestrating an immune response, are also suppressed in CRC (136). Tumor-derived IL-6, stimulated in part by leptin, promotes accumulation of myeloid-derived suppressor cells (MDSCs) (139) and upregulates dendritic cell expression of arginase (136), both processes that attenuate CD4 + and CD8 + T cell responses.…”

“…Dendritic cells, key players in orchestrating an immune response, are also suppressed in CRC (136). Tumor-derived IL-6, stimulated in part by leptin, promotes accumulation of myeloid-derived suppressor cells (MDSCs) (139) and upregulates dendritic cell expression of arginase (136), both processes that attenuate CD4 + and CD8 + T cell responses. Obesity also increases adipose-derived granulocyte-macrophage colony-stimulating factor (GM-CSF), which restricts T cell receptor repertoire and compromises T cell function (140).…”

The Role of PDGFs and PDGFRs in Colorectal Cancer

“…Tumor microenvironment (TME) represents a new hallmark of cancer [3] and includes complex cooperation between tumor cells with stroma, immune cells, and endothelial cells. Moreover, the presence of inflammatory cells and inflammatory mediators such as chemokines and cytokines related to TME facilitate tumor progression, including CRC [4]. Sometimes, a single cytokine (e.g., growth factor) can activate signals of complex molecular cascades resulting in tumor progression and development.…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…[44] The study was terminated due to the occurrence of the side effects and the lack of efficacy in disease progression. [46][47][48] www.advancedsciencenews.com www.advtherap.com Structurally related to NAMI-A are KP1019 [49,50] and its watersoluble formulation (N)KP1339 (Figure 1), and both underwent phase I clinical investigations in patients with solid tumors. [22] Cytotoxicity studies of NAMI-A and other experimental ruthenium-based drugs showed that simple in vitro (monolayer or co-culture) results are a poor indicator of in vivo activity.…”