Unlocking the therapeutic potential of primary tumor-draining lymph nodes

Rotman, Jossie; Koster, Bas D.; Jordanova, Ekaterina S.; Heeren, A. Marijne; Gruijl, Tanja D. de

doi:10.1007/s00262-019-02330-y

Cited by 61 publications

(57 citation statements)

References 57 publications

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Section: Introductionmentioning

confidence: 99%

“…Human malignant tumors have developed a variety of biochemical mechanisms which allow them to escape host immune surveillance, thus leading to disease progression (1, 2). This applies to both liquid and solid tumors (1). It has recently become evident that acute myeloid leukemia (AML) cells, originating from self-renewing myeloid haematopoietic precursors, operate an immunosuppressive pathway which includes facilitation of exocytosis of the T cell immunoglobulin and mucin domain containing protein 3 (Tim-3) and its natural ligand, galectin-9 (2–4).…”

Section: Introductionmentioning

confidence: 99%

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The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

et al. 2019

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Human cancer cells operate a variety of effective molecular and signaling mechanisms which allow them to escape host immune surveillance and thus progress the disease. We have recently reported that the immune receptor Tim-3 and its natural ligand galectin-9 are involved in the immune escape of human acute myeloid leukemia (AML) cells. These cells use the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3, and possibly other ligands) to trigger the pathway. We hypothesized that the Tim-3-galectin-9 pathway may be involved in the immune escape of cancer cells of different origins. We found that studied breast tumors expressed significantly higher levels of both galectin-9 and Tim-3 compared to healthy breast tissues of the same patients and that these proteins were co-localized. Increased levels of LPHN2 and expressions of LPHN3 as well as FLRT3 were also detected in breast tumor cells. Activation of this pathway facilitated the translocation of galectin-9 onto the tumor cell surface, however no secretion of galectin-9 by tumor cells was observed. Surface-based galectin-9 was able to protect breast carcinoma cells against cytotoxic T cell-induced death. Furthermore, we found that cell lines from brain, colorectal, kidney, blood/mast cell, liver, prostate, lung, and skin cancers expressed detectable amounts of both Tim-3 and galectin-9 proteins. The majority of cell lines expressed one of the LPHN isoforms and FLRT3. We conclude that the Tim-3-galectin-9 pathway is operated by a wide range of human cancer cells and is possibly involved in prevention of anti-tumor immunity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

et al. 2019

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“…However, cancer-derived immune-repressive factors such as extracellular vesicles, IL-6, TGF-β, prostaglandin-E2 (PGE2), and vascular endothelial growth factor (VEGF) make the TDLN immune response compromised. As a result, DC maturation gets suppressed and acquires M2 macrophage-like phenotype, and will, therefore, result in improper cross-present tumor antigens in TDLN ( Rotman et al., 2019 ). Tumor microenvironment (TME) in TDLN supports tumor growth and survival and regulates immune responses.…”

Section: Introductionmentioning

confidence: 99%

Galunisertib Drives Treg Fragility and Promotes Dendritic Cell-Mediated Immunity against Experimental Lymphoma

et al. 2020

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Summary Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor-I activation, currently under clinical trial in a variety of cancers. We have tested the combined effects of galunisertib- and interleukin-15-activated dendritic cells in an aggressive and highly metastatic murine lymphoma. Based on the tumor-draining lymph node architecture, and its histology, the combination therapy results in better prognosis, including disappearance of the disease-exacerbating regulatory T cells. Our data suggest that galunisertib significantly enhances the success of immunotherapy with IL-15-activated dendritic cells by limiting the regulatory T cells generation with consequent downregulation of regulatory T cells in the tumor-draining lymph nodes and vascularized organ like spleen. This is also associated with consistent loss p-SMAD2 and downregulation of Neuropilin-1, leading to better prognosis and positive outcome. These results connect the role of combined therapy with the consequent elimination of disease-exacerbating T regulatory cells in a metastatic murine lymphoma.

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“…Tumor-draining lymph nodes (TDLNs) are critical site for generating tumor-specific immune responses [34]. Unfortunately, TDLNs are directly influenced by tumor-derived immunosuppressive factors, which lead to impaired DC maturation.…”

Section: Tae Vaccines Improved Tumor Immune Microenvironment In Tumentioning

confidence: 99%

Tumor Cell-associated Exosomes Robustly Elicit Anti-tumor Immune Responses through Modulating Dendritic Cell Vaccines in Lung Tumor

Huang

Wang

et al. 2020

Int. J. Biol. Sci.

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DC vaccine-based immunotherapy is emerging as a novel therapeutic strategy for cancer treatment, however, antitumor effect of DC vaccines based on tumor cell lysates (TCLs) remains unsatisfactory due to poor immunogenicity of tumor antigens. Although tumor-associated exosomes (TAEs) have been reported as a promising antigen for DC vaccines, it remains unclear how TAE-based DC vaccine induced antitumor immunity in lung cancer. Methods: In the present study, we extracted TAEs from the supernatant of tumor cell culture medium, and compared the effect of TAEs with TCLs on DCs. To further evaluate the therapeutic effect of DCTAE, we used immunofluorescence and flow cytometry to evaluate the apoptosis of tumor tissue, tumor-infiltrating CD8 + T cells and Tregs in TDLNs and spleen. Then the levels of cytokines of IL-12, IFN-γ, L-10 and TGF-β were quantified by ELISA assays. Results: Our data showed that TAEs were more potent than TCLs to promote DC maturation and enhance MHC cross presentation, which directly contributed to more robust tumor-specific cytotoxic T lymphocyte (CTL) response. More importantly, TAEs reduced the expression of PD-L1 of DCs, thereby led to down-regulated population of Tregs in vitro. Moreover, DCTAE remarkably suppressed the tumor growth and prolonged survival rate in vivo, due to participance of CD8 + T cells and decreased Tregs in TDLNs and spleen. Conclusion: TAEs could serve to improve vaccine-elicited immunotherapy by triggering stronger DC-mediated immune responses and decreasing Tregs in the tumor microenvironment.

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Unlocking the therapeutic potential of primary tumor-draining lymph nodes

Cited by 61 publications

References 57 publications

The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

Galunisertib Drives Treg Fragility and Promotes Dendritic Cell-Mediated Immunity against Experimental Lymphoma

Tumor Cell-associated Exosomes Robustly Elicit Anti-tumor Immune Responses through Modulating Dendritic Cell Vaccines in Lung Tumor

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