Control of Dendritic Cell Function Within the Tumour Microenvironment

Abstract

The tumour microenvironment (TME) presents a major block to anti-tumour immune responses and to effective cancer immunotherapy. The inflammatory mediators such as cytokines, chemokines, growth factors and prostaglandins generated in the TME alter the phenotype and function of dendritic cells (DCs) that are critical for a successful adaptive immune response against the growing tumour. In this mini review we discuss how tumour cells and the surrounding stroma modulate DC maturation and trafficking to impact T cell function. Fibroblastic stroma and the associated extracellular matrix around tumours can also provide physical restrictions to infiltrating DCs and other leukocytes. We discuss interactions between the inflammatory TME and infiltrating immune cell function, exploring how the inflammatory TME affects generation of T cell-driven anti-tumour immunity. We discuss the open question of the relative importance of antigen-presentation site; locally within the TME versus tumour-draining lymph nodes. Addressing these questions will potentially increase immune surveillance and enhance anti-tumour immunity.

Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target

“…Although several preclinical studies have suggested an immunosuppressive function of mregDCs within the TME, reports are still lacking relating tumour‐infiltrating mregDCs with poor prognosis and immunotherapy resistance in cancer patients. 82 This phenomenon may be due to the lack of a unified definition standard for mregDCs, which has resulted in multiple and complex names in different studies; these names include LAMP3 + CCR7 + cells, CD45 + Lin − MHC‐II + CD11c + CD80 hi CD274 hi , and LAMP3 + IDO1 + CCL19 + cells. Furthermore, the annotation of mregDCs in single‐cell studies involves a series of genes, while previous relevant studies could not precisely define mregDCs due to the limitations of the experimental technology.…”

Targeted mechanical forces enhance the effects of tumor immunotherapy by regulating immune cells in the tumor microenvironment

“…DCs are the initiator of the body’s immune response, and their primary characteristic is stimulation of primary T cell proliferation. The fibroblast matrix and the associated ECM around the tumor provide physical constraints on infiltrating DCs, and regulate DC maturation and trafficking, thereby influencing T-cell function 95 . Myelofibrosis is believed to promote the pathological remodeling of the ECM, and studies have confirmed that the physical and mechanical properties of myelofibrosis contribute to the abnormal differentiation of monocytes, thus causing proinflammatory polarization of monocytes and differentiation into DCs 96 .…”

Dendritic cells and natural killer cells: The road to a successful oncolytic virotherapy

“…OVs are also responsible for the activation of additional immune responses, which serve to counterbalance the decrease in the presentation of tumor antigens and to boost the interaction of APCs with T cells that are specific to the tumor ( 117 ). For instance, several soluble substances released in the TME, including IL-6, IL-10, IDO, M-CSF, transforming growth factor-β1 (TGF-β1), PGE2, and VEGF, can assist the immunosuppression of tumor-infiltrating DCs ( 118 ). IL-6 knockout mice ( 119 ), anti-VEGF antibodies ( 120 , 121 ), and anti-IL-8 monoclonal antibodies improved immune control in a series of animal models, resulting in an improved immune response to tumors ( 122 , 123 ).…”

“…IL-6 knockout mice ( 119 ), anti-VEGF antibodies ( 120 , 121 ), and anti-IL-8 monoclonal antibodies improved immune control in a series of animal models, resulting in an improved immune response to tumors ( 122 , 123 ). However, pro-inflammatory cytokines are also present in the TME, which helps to improve DC maturation, enhance antigen priming, and boost immune infiltration in malignancies ( 118 ). Consequently, the intricate balance of inflammatory signals in the TME is a topic of significant study interest but is currently difficult to focus.…”