Radiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined... Show moreRadiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined in clinical studies, although their success has been limited. We used mouse tumor models to understand how radiotherapy induces T cell priming and subsequent anti-tumor immunity. In a model resembling lymphocyte-depleted cancer, we identified obstacles to systemic radiotherapy-induced T cell responses and proposed interventions to overcome them. Additionally, we explored strategies to counter local T cell suppression in the tumor microenvironment. In poorly immunogenic tumors, radiotherapy can provoke a T cell response, but this is counteracted by the generation of immunosuppressive Tregs. Combining radiotherapy with checkpoint immunotherapy, despite its success in humans, unexpectedly amplified the Treg response, further hindering cytotoxic T-cell activity. Our findings suggest this immunotherapy may not benefit these cancers. We discovered that molecules like CD80 and CD86, capable of stimulating T cells via the CD28 receptor, have distinct roles in promoting cytotoxic and Treg cells. Blocking CD86 enhanced cytotoxic T cell responses post-radiotherapy, leading to tumor rejection. Our study elucidates how tumor characteristics shape T-cell responses, how radiotherapy can evoke both favorable and unfavorable responses, and how targeted antibody immunotherapy can influence this interplay. Show less
Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications,... Show moreDendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8(+)/CD4(+) T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications. Show less
Dendritic cells are the canonical professional antigen-presenting cell and are therefore crucial in the generation of efficient adaptive T cell responses. It is now well described that immune cells... Show moreDendritic cells are the canonical professional antigen-presenting cell and are therefore crucial in the generation of efficient adaptive T cell responses. It is now well described that immune cells – including dendritic cells – make drastic changes to their biology to transition between different life stages and to deal efficiently with the threat of infection. However, an unanswered question was if DCs with different T cell polarizing properties - that is to say they preferentially skew T cells towards a specific specialization (for example T helper 1 cells over T helper 2 cells) - rely on distinct metabolic characteristics for their T cell polarizing ability. This thesis tries to address that question by studying the metabolism of dendritic cells after in vitro stimulation with antigens or immunomodulatory compounds that are known to prime either T helper 1 cells, T helper 2 cells, T helper 17 cells or regulatory T cells. In addition, we interrogate the role of liver kinase B1 (LKB1) and mechanistic target of rapamycin complex 1 (mTORC1) in DC biology. Show less
Saris, A.; Steuten, J.; Schrijver, D.P.; Schijndel, G. van; Zwaginga, J.J.; Ham, S.M. van; Brinke, A. ten 2021
Platelet transfusions are a frequently administered therapy for especially hemato-oncological patients with thrombocytopenia. Next to their primary function in hemostasis, currently there is... Show morePlatelet transfusions are a frequently administered therapy for especially hemato-oncological patients with thrombocytopenia. Next to their primary function in hemostasis, currently there is increased attention for the capacity of platelets to affect the function of various cells of the immune system. Here, we investigate the capacity of platelets to immuno-modulate monocyte-derived dendritic cells (moDC) as well as primary dendritic cells and effects on subsequent T cell responses. Platelets significantly inhibited pro-inflammatory (IL-12, IL-6, TNF alpha) and increased anti-inflammatory (IL-10) cytokine production of moDCs primed with toll-like receptor (TLR)-dependent and TLR-independent stimuli. Transwell assays and ultracentrifugation revealed that a soluble factor secreted by platelets, but not microvesicles, inhibited DC activation. Interestingly, platelet-derived soluble mediators also inhibited cytokine production by human ex vivo stimulated myeloid CD1c+ conventional DC2. Moreover, platelets and platelet-derived soluble mediators inhibited T cell priming and T helper differentiation toward an IFN gamma+ Th1 phenotype by moDCs. Overall, these results show that platelets are able to inhibit the pro-inflammatory properties of DCs, and may even induce an anti-inflammatory DC phenotype, with decreased T cell priming capacity by the DC. The results of this study provide more insight in the potential role of platelets in immune modulation, especially in the context of platelet transfusions. Show less
