Interactions of tumor cells with dendritic cells: balancing immunity and tolerance

Tang

Cancer Immunology Research

et al. 2015

118

149

Tumor antigens and innate signals are vital considerations in developing new therapeutic or prophylactic antitumor vaccines. The role or requirement of intact tumor cells in the development of an effective tumor vaccine remains incompletely understood. This study reveals the mechanism by which tumor cell-derived microparticles (T-MP) can act as a cell-free tumor vaccine. Vaccinations with T-MPs give rise to prophylactic effects against the challenge of various tumor cell types, while T-MP-loaded dendritic cells (DC) also exhibit therapeutic effects in various tumor models. Such antitumor effects of T-MPs are perhaps attributable to their ability to generate immune signaling and to represent tumor antigens. Mechanically, T-MPs effectively transfer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. In turn, type I IFN promotes DC maturation and presentation of tumor antigens to T cells for antitumor immunity. These findings highlight a novel tumor cell-free vaccine strategy with potential clinical applications.

Section: Introductionmentioning

confidence: 99%

Cell-free Tumor Microparticle Vaccines Stimulate Dendritic Cells via cGAS/STING Signaling

Tang

Cancer Immunology Research

et al. 2015

118

149

“…Alternatively, antigens can enter the lymph, reach the nodal marginal sinus and therein be captured and processed by nodal resident antigen-presenting cells 5 . In a clinically apparent tumour mass, however, the spontaneous immune response regularly fails to achieve a complete elimination of cancer cells, with DCs losing their adjuvant function and, similar to many other immune and non-immune cells, acquiring a tumour-promoting programme that sustains tumour escape 4,[6][7][8] .…”

mentioning

confidence: 99%

“…DCs promote protective immunity by capturing antigens at the primary tumour site, migrating to lymph nodes via lymphatic vessels, and ultimately presenting these tumour-derived antigens to nodal naive T cells 1,2,4 . Alternatively, antigens can enter the lymph, reach the nodal marginal sinus and therein be captured and processed by nodal resident antigen-presenting cells 5 .…”

mentioning

confidence: 99%

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

et al. 2014

Dendritic cells (DCs) initiate adaptive immune responses to cancer cells by activating naive T lymphocytes. 6-sulfo LacNAc þ DCs (slanDCs) represent a distinct population of circulating and tissue proinflammatory DCs, whose role in cancer immune surveillance is unknown. Herein, by screening a large set of clinical samples, we demonstrate accumulation of slanDCs in metastatic tumour-draining lymph nodes (M-TDLN) from carcinoma patients. Remarkably, slanDCs are absent at the primary carcinoma site, while their selective nodal recruitment follows the arrival of cancer cells to M-TDLN. slanDCs surround metastatic carcinoma deposits in close proximity to dead cells and efficiently phagocytose tumour cells. In colon carcinoma patients, the contingent of circulating slanDCs remains intact and competent in terms of IL-12p70 and tumour necrosis factor alpha production, induction of T-cell proliferation and migratory capacity to a set of chemokines produced in M-TDLN. We conclude that activated slanDCs represent previously unrecognized players of nodal immune responses to cancer cells.

Current Opinion in Immunology

“…Recognition, uptake and presentation of dying cells by DCs plays a critical role in immunologic consequences of cell death [30]. Uptake of opsonized cells and immune complexes depends on both Fc receptors and complement system.…”

Section: Role Of Fcγr Balance In Adaptive Immunitymentioning

confidence: 99%

Role of chaperones and FcγR in immunogenic death

Dhodapkar

2008

Cell death under physiologic conditions does not lead to the induction of immunity. However recognition of stressed or opsonized cells can trigger immune responses. Recent studies have begun to illustrate the critical role of molecular chaperones such as inducible heat shock proteins in mediating immunogenicity of stressed cells. Immunity to opsonized cells depends in part on the engagement and the balance of activating and inhibitory FcγRs on antigen presenting dendritic cells. Understanding both these pathways of immunogenic cell death may yield novel approaches to regulate immunity. Two forms of immunogenic cell deathBillions of cells die each day and are replaced by newly differentiated progeny. Corpses of such dying cells are rapidly removed by phagocytes; do not elicit immunity and may induce tolerance. However under some settings, recognition of dying cells leads to inflammatory responses and immunity[1] • . Two aspects of such "immunogenic death" are the focus of this review. A common response to cellular stress is the transcriptional activation of molecular chaperones that belong to the class of inducible heat shock proteins (HSPs). Another setting wherein dying cells might induce immunity is when they are opsonized by antibodies due to antibody mediated recognition of determinants on dying cells. Such opsonized cells can be recognized by FcγR mediated pathways on antigen presenting cells (APCs). Below, we will discuss recent insights into how both of these pathways play an important role in regulating immunogenicity of dying cells and can be dysregulated in autoimmunity. Heat shock proteins (HSPs) and immunogenic cell deathHSPs are referred to as stress proteins or molecular chaperones, although most HSPs are constitutively expressed. Known best for their roles in regulating intracellular protein homeostasis, HSPs were immunologically implicated because of the observations that tumor-derived HSPs, although having no tumor-specific mutations, can immunize for tumor-specific T cell immunity [2] • . Efforts to explain the phenomenon have led to two