Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer

Ayala, Mariela A. Moreno; Gottardo, María Florencia; Gori, María Soledad; Candia, Alejandro Javier Nicola; Caruso, Carla Mariana; Laurentiis, Andrea De; Imsen, Mercedes; Klein, Slobodanka; Joffé, Elisa Bal de Kier; Salamone, Gabriela; Castro, Maria G.; Seilicovich, Adriana

doi:10.1007/s00432-017-2421-7

Cited by 15 publications

(14 citation statements)

References 114 publications

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“…Poor clinical responses to some TLR ligands and tumour vaccines might arise in part because increased IDO activity dampens the innate immune adjuvant effects of these treatments 112,113 .…”

Section: [H2] Immune Balance and Adverse Responses To Therapymentioning

confidence: 99%

Immune control by amino acid catabolism during tumorigenesis and therapy

et al. 2019

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Immune checkpoints arise from physiologic changes during tumourigenesis that re-programme inflammatory, immunologic and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunologic tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) are common TME hallmarks at clinical presentation of cancer. Cells catabolising Trp and Arg suppress effector T cells and stabilize regulatory T cells (Tregs) to suppress immunity in chronic inflammatory diseases of clinical significance, including cancers.Processes that induce Trp and Arg catabolism in the TME remain incompletely defined.Indoleamine 2,3 dioxygenase (IDO) and arginase (ARG1), which catabolise Trp and Arg respectively, respond to inflammatory cues including interferons (IFNs) and TGFβ cytokines.Dying cells generate inflammatory signals including DNA, which is sensed to stimulate the production of type I IFNs via the Stimulator of Interferon Genes (STING) adaptor. Thus, dying cells help establish local conditions that suppress anti-tumour immunity to promote tumourigenesis. Here we review evidence that Trp and Arg catabolism contributes to inflammatory processes that promote tumourigenesis, impede immune responses to therapy and might promote neurologic comorbidities associated with cancer.

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“…Poor clinical responses to some TLR ligands and tumour vaccines might arise in part because increased IDO activity dampens the innate immune adjuvant effects of these treatments 112,113 .…”

Section: [H2] Immune Balance and Adverse Responses To Therapymentioning

confidence: 99%

Immune control by amino acid catabolism during tumorigenesis and therapy

et al. 2019

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“…289 Moreno Ayala et al (from Universidad de Buenos Aires, Buenos Aires, Paraguay) combined DC vaccines with different TLR7 or TLR9 agonists, observing that whereas DCs activated through TLR9 enabled prolonged tumor-and metastasis-free survival, dual TLR7/TLR9 activation impaired vaccination efficacy, a disparity that could be ameliorated by inhibiting nitric oxide synthase (NOS) and indoleamine-pyrrole-2,3-dioxygenase 1 (IDO1). 290,291 Ebrahimi-Nik et al (from University of Connecticut, Farmington, CT, USA) reported DCs to be superior to macrophages at eliciting neoantigen-targeted eradicating immunity in a DC vaccination setup, but surprisingly found CD11c + MHC-II low DCs to be the best APCs in this particular setting. 26 Montico et al (from Centro di Riferimento Oncologico, Aviano, Italy) pulsed human DCs with mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL) cells undergoing immunogenic cell death (ICD) 292,293 in response to 9-cis-retinoic acid plus type I IFN, which mediated robust anticancer immunity upon inoculation in immunodeficient tumor-bearing mice reconstituted with human peripheral blood mononuclear cells (PBMCs).…”

Section: Recent Preclinical Developmentsmentioning

confidence: 99%

Trial watch: dendritic cell vaccination for cancer immunotherapy

et al. 2019

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Dendritic-cells (DCs) have received considerable attention as potential targets for the development of anticancer vaccines. DC-based anticancer vaccination relies on patient-derived DCs pulsed with a source of tumorassociated antigens (TAAs) in the context of standardized maturation-cocktails, followed by their reinfusion. Extensive evidence has confirmed that DC-based vaccines can generate TAA-specific, cytotoxic T cells. Nonetheless, clinical efficacy of DC-based vaccines remains suboptimal, reflecting the widespread immunosuppression within tumors. Thus, clinical interest is being refocused on DC-based vaccines as combinatorial partners for T cell-targeting immunotherapies. Here, we summarize the most recent preclinical/clinical development of anticancer DC vaccination and discuss future perspectives for DC-based vaccines in immunooncology.

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“…injection of tumor cells in Ref. 31 vs. our s.c. TNBC model that develops spontaneous lung metastases 32 , or the use of immunosuppressed hosts 26,33 vs. our immune-competent mouse model. Since the analog HNG has shown higher affinity by membrane HN receptors and a more potent antiapoptotic effect than HN in several cell types 34 , it is possible that in vivo HN and HNG could interact differently with the receptors present in tumor and stromal cells.…”

Section: Discussionmentioning

confidence: 99%

“…cell viability assay (Mtt). 4T1 and MDA-MB-231 cells were incubated in medium with FBS with different doses of DOXO for 72 h and cell viability was assessed as previously described (Supplementary Information) 18,32 .…”

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Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Ayala

Gottardo

Zuccato

et al. 2020

Sci Rep

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Humanin (HN) is a mitochondrial-derived peptide with cytoprotective effect in many tissues. Administration of Hn analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the effect of HN on the progression of experimental triple negative breast cancer (tnBc). the meta-analysis of transcriptomic data from the cancer Genome Atlas indicated that Hn and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of Hn in tnBc biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous Hn protected tnBc cells from apoptotic stimuli whereas shRnA-mediated Hn silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic effect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These findings suggest that HN may exert pro-tumoral effects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer. Breast cancer is the most common cause of death by cancer in women 1. Although new strategies have been developed for the treatment of breast tumors that express hormone receptors and/or human epidermal growth factor receptor 2 (Her2), there are no therapeutic options for patients with triple negative breast cancer (TNBC), for whom chemotherapy/radiotherapy remains the first-line treatment 2,3. Since these tumors frequently develop chemo-resistance 4 , novel therapeutic targets are urgently needed to improve the treatment of TNBC. A cytoprotective mitochondrial-derived peptide, humanin (HN), was discovered in healthy neurons of patients suffering Alzheimer's disease 5. HN was the first small open reading frame (ORF) identified within the mitochondrial DNA, encoded within the 16S rRNA gene (MT-RNR2) 6. HN can be translated both in the mitochondrial matrix or the cytosol, resulting in biologically functional 21 and 24-amino acid peptides, respectively 7. Small ORFs for six other small HN-like peptides (SHLPs) have been detected in the mitochondrial genome, two of which (SHLP2 and SHLP3) exhibit biological activity 8. Thirteen MT-RNR2-like loci that encode for fifteen HN-like peptides were detected in the nuclear genome 9. However, the expression of the mitochondrial gene MT-RNR2 is substantially higher than any nuclear isoform 9. HN regulates the mitochondrial apoptotic pathway by interaction with proteins of the Bcl-2 family 10. Intracellular HN binds to proapoptotic proteins, such as Bax, tBid and BimEL inhibiting the release of cytochrome

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Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer

Cited by 15 publications

References 114 publications

Immune control by amino acid catabolism during tumorigenesis and therapy

Immune control by amino acid catabolism during tumorigenesis and therapy

Trial watch: dendritic cell vaccination for cancer immunotherapy

Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

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