Tumor ablation technologies, such as radiofrequency-, cryo- or high-intensity focused ultrasound (HIFU) ablation will destroy tumor tissue in a minimally invasive manner. Ablation generates large ...volumes of tumor debris in situ, releasing multiple bio-molecules like tumor antigens and damage-associated molecular patterns. To initiate an adaptive antitumor immune response, antigen-presenting cells need to take up tumor antigens and, following activation, present them to immune effector cells. The impact of the type of tumor ablation on the precise nature, availability and suitability of the tumor debris for immune response induction, however, is poorly understood. In this review, we focus on immune effects after HIFU-mediated ablation and compare these to findings using other ablation technologies. HIFU can be used both for thermal and mechanical destruction of tissue, inducing coagulative necrosis or subcellular fragmentation, respectively. Preclinical and clinical results of HIFU tumor ablation show increased infiltration and activation of CD4
+
and CD8
+
T cells. As previously observed for other types of tumor ablation technologies, however, this ablation-induced enhanced infiltration alone appears insufficient to generate consistent protective antitumor immunity. Therapies combining ablation with immune stimulation are therefore expected to be key to boost HIFU-induced immune effects and to achieve systemic, long-lasting, antitumor immunity.
Sialic acids sweeten a tumor's life Büll, Christian; Stoel, Marieke A; den Brok, Martijn H ...
Cancer research (Chicago, Ill.),
06/2014, Letnik:
74, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Over four decades ago, specific tumor characteristics were ascribed to the increased expression of sialic acid sugars on the surface of cancer cells, and this led to the definition of sialic acids as ...potential therapeutic targets. Recent advances in glycobiology and cancer research have defined the key processes underlying aberrant expression of sialic acids in cancer, and its consequences, more precisely. These consequences include effects on tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. Collectively, these novel insights provide further rationale for the design and development of therapeutic approaches that interfere with excessively high expression of sialic acids in cancer cells. Strategies to target aberrant sialylation in cancer, however, have evolved comparatively slowly. Here, we review recent findings that emphasize the detrimental effects of hypersialylation on multiple aspects of tumor growth and behavior. We also discuss novel therapeutic strategies.
Lipid droplets (LDs) were initially described as fat storage organelles in adipocytes, but are increasingly recognized as dynamic players in lipid metabolism, with important roles not only in ...diseases such as diabetes and cancer, but also in immune regulation. Alterations in immune cell function, such as myeloid cell activation, are connected to profound changes in LD numbers and LD protein composition. Thus, these organelles appear to be essential to metabolically support immune responses, and have a vital role in antigen crosspresentation, interferon (IFN) responses, production of inflammatory mediators, and pathogen clearance. Here, we review recent studies that report on the role of LDs in the modulation of immune cell function, primarily focusing on myeloid cells, such as macrophages and dendritic cells (DCs).
LDs are intracellular energy storage organelles, but studies in macrophages and, more recently, DCs have highlighted their role in immune regulation. For example, LDs have a critical role in IFN responses and antigen crosspresentation.
Different LDs, with unique protein or lipid compositions, appear to exist in specific cells or even within one cell. Different types of immune activation are also reflected by modification of the LD profiles, tied to changes in cellular metabolism.
Although the presence of LDs mostly appears to be correlated with positive immunological outcome, the LDs found in cancer or upon exposure to oxidized lipids are associated with unproductive immune responses.
Tumor-destructing techniques, like radiofrequency ablation (RFA), allow eradication of large tumors. Potentially, in situ tumor destruction also can provide the immune system with an antigen source ...for the induction of antitumor immunity. Antigen-presenting cells could take up antigens in the periphery after which they induce specific immune responses. Recent data show that especially antigen-presenting dendritic cells are crucial for the induction of potent immune responses. However, virtually nothing is known regarding the induction of immune responses after in situ tumor destruction in mice or humans. We used the well-defined murine B16-OVA melanoma cell line to develop a novel tumor model to explore: (a). the immunologic consequences of in situ tumor destruction; and (b). the efficacy of a combination approach of tumor destruction and immunostimulation. Applying this model system we demonstrate that following RFA, a weak but detectable immune response develops, directed against OVA, but also against a broader range of B16 antigens. Adoptive transfer experiments further indicate that antitumor reactivity can be transferred to naïve mice by splenocytes. To augment the response observed, we administered a blocking monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 at the time of tumor destruction. Interestingly, this strongly enhanced antitumor immunity, resulting in long-lasting tumor protection. These results illustrate that in situ tumor destruction can provide a useful antigen source for the induction of antitumor immunity, provided that additional immunostimulatory signals are coadministered.
The best known method of high-intensity focused ultrasound is thermal ablation, but interest in non-thermal, mechanical destruction is increasing. The advantages of mechanical ablation are that ...thermal protein denaturation remains limited and less damage is created to the surrounding tissue by thermal diffusion. The two main techniques for mechanical fragmentation of tissue are histotripsy and boiling histotripsy. These techniques can be used for complete liquefaction of tumor tissue into submicron fragments, after which the fragmented tissue can be easily removed by natural (immunologic) responses. Interestingly it seems that there is a correlation between the degree of destruction and tissue specific characteristics based on the treatment settings used. In this review article, the technical aspects of these two techniques are described, and an overview of the in vivo pathologic and immunologic responses is provided.
Current multimodal treatments for patients with neuroblastoma (NBL), including anti‐disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around ...only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well‐explored autologous mouse model for NBL is the TH‐MYCN model. However, the immunobiology of the TH‐MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH‐MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH‐MYCN‐derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild‐type and Rag1−/− mice, showing an important role for NK cells in the natural anti‐NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti‐GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH‐MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients.
What's new?
Natural killer (NK) cells may serve a role in immune defense against neuroblastoma, though limitations in existing models have prevented extensive study of the immunological characteristics of the disease. Here, to better understand the immunobiology of neuroblastoma, the TH‐MYCN mouse model was adapted for immunological investigation. Tumor cells (9464D) derived from immunologically compatible C57Bl/6 TH‐MYCN mice were found to express the tumor antigen GD2. In addition, depletion of NK cells was associated with tumor outgrowth in both wild‐type and Rag1‐/‐ C57Bl/6 mice, whereas immunotherapy targeted against GD2 decreased tumor growth.
Sialic acid sugars that terminate cell‐surface glycans form the ligands for the sialic acid binding immunoglobulin‐like lectin (Siglec) family, which are immunomodulatory receptors expressed by ...immune cells. Interactions between sialic acid and Siglecs regulate the immune system, and aberrations contribute to pathologies like autoimmunity and cancer. Sialic acid/Siglec interactions between living cells are difficult to study owing to a lack of specific tools. Here, we report a glycoengineering approach to remodel the sialic acids of living cells and their binding to Siglecs. Using bioorthogonal chemistry, a library of cells with more than sixty different sialic acid modifications was generated that showed dramatically increased binding toward the different Siglec family members. Rational design reduced cross‐reactivity and led to the discovery of three selective Siglec‐5/14 ligands. Furthermore, glycoengineered cells carrying sialic acid ligands for Siglec‐3 dampened the activation of Siglec‐3+ monocytic cells through the NF‐κB and IRF pathways.
Clicking the immune system off: We report a method to rapidly reprogram the binding of sialic acid sugars on living cells to their cognate Siglec receptors through glycoengineering and click chemistry. Binding could be improved by more than 100‐fold and in a selective manner. The modified cells showed potent immunosuppressive activity resulting from strong signaling through Siglecs on immune cells.
Saponin-based adjuvants (SBAs) are being used in animal and human (cancer) vaccines, as they induce protective cellular immunity. Their adjuvant potency is a factor of inflammasome activation and ...enhanced antigen cross-presentation by dendritic cells (DCs), but how antigen cross-presentation is induced is not clear. Here we show that SBAs uniquely induce intracellular lipid bodies (LBs) in the CD11b+ DC subset in vitro and in vivo. Using genetic and pharmacological interference in models for vaccination and in situ tumour ablation, we demonstrate that LB induction is causally related to the saponin-dependent increase in cross-presentation and T-cell activation. These findings link adjuvant activity to LB formation, aid the application of SBAs as a cancer vaccine component, and will stimulate development of new adjuvants enhancing T-cell-mediated immunity.
Sialic acids represent a family of sugar molecules derived from neuraminic acid that frequently terminate glycan chains and contribute to many biological processes. Already five decades ago, ...aberrantly high expression of sialic acids has been proposed to protect cancer cells from recognition and eradication by the immune system. Today, increased understanding at the molecular level demonstrates the broad immunomodulatory capacity of tumor-derived sialic acids that is, at least in part, mediated through interactions with immunoinhibitory Siglec receptors. Here we will review current studies from a sialic acid sugar perspective showing that tumor-derived sialic acids disable major killing mechanisms of effector immune cells, trigger production of immune suppressive cytokines and dampen activation of antigen-presenting cells and subsequent induction of anti-tumor immune responses. Furthermore, strategies to modulate sialic acid expression in cancer cells to improve cancer immunotherapy will be discussed.
•Aberrant high expression of sialic acids on tumor cells facilitates immune evasion.•Tumors utilize the immune suppressive sialic acid/Siglec axis.•Tumor sialic acids protect from CTL and NK cell cytotoxicity.•Tumor sialoglycans modulate myeloid cell function and dampen dendritic cell activation.•Modulating aberrant sialylation in tumor cells could boost cancer immunotherapy.
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