Anti-tumor activity of CpG-ODN aerosol in mouse lung metastases

Studies in preclinical models have demonstrated the superior anti-tumor effect of CpG oligodeoxynucleotides (CpG-ODN) when administered at the tumor site rather than systemically. We evaluated the effect of aerosolized CpG-ODN on lung metastases in mice injected with immunogenic N202.1A mammary carcinoma cells or weakly immunogenic B16 melanoma cells. Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-γ and IL-1β and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice. Treatment with aerosolized CpG-ODN induced an expansion of CD4+ cells in lung and was more efficacious than systemic i.p. administration against experimental lung metastases of immunogenic N202.1A mammary carcinoma cells, whereas only i.p. delivery of CpG-ODN provided anti-tumor activity, which correlated with NK cell expansion in the lung, against lung metastases of the poorly immunogenic B16 melanoma. The inefficacy of aerosol therapy to induce NK expansion was related to the presence of immunosuppressive macrophages in B16 tumor-bearing lungs, as mice depleted of these cells by clodronate treatment responded to aerosol CpG-ODN through expansion of the NK cell population and significantly reduced numbers of lung metastases. Our results indicate that tumor immunogenicity and the tumor-induced immunosuppressive environment are critical factors to the success of CpG therapy in the lung, and point to the value of routine sampling of the lung immune environment in defining an optimal immunotherapeutic strategy

Identification Of New Molecules Involved In Dendritic Cell Localization

The present study was designed to investigate the expression and function of an orphan seven transmembrane receptor named CCRL2 (CC chemokine receptor like 2), a putative chemokine receptor. In human tissues CCRL2 was expressed mainly by lung, lymphoid tissues and fetal spleen. Among leukocytes CCRL2 was expressed by monocytes, neutrophils and dendritic cells (DC). Because chemokines play a fundamental role in DC trafficking, modulation of CCLR2 expression in this cell type was further investigated. Maturative stimuli like LPS and CD40L strongly up regulated CCRL2 mRNA and protein in DC. Culture of DC in the presence of inhibitors of maturation and function such as VitD3 and Dex had no effect on LPS-induced CCRL2 up regulation. On the contrary PGE2, that does not affect DC maturation, completely abolished LPS induction of CCRL2 expression. The effect of LPS and CD40L on CCRL2 expression was rapid (1.5h) and transient (maximal at 4h) and declined by 24h, conversely the upregulation of CCR7 that was slower and reached a plateau at 24h of stimulation. Since CCRL2 gene is located in the main chemokine receptor cluster in the 3p21 chromosome, it is likely to be a conventional inflammatory chemokine receptor. In order to identify ligands CCRL2 transfectants were used in chemotaxis and calcium flux assays with a broad panel of inflammatory CC and CXC chemokines but no ligand was identified. The alterations in the DRYLAR/IV motif in the second intracellular loop suggest that CCRL2 may be a candidate for the family of chemokine decoy receptors like the receptor D6. This second hypothesis was evaluated performing chemokine scavenging assays. None of the chemokine tested was scavenged by CCRL2. However in parallel experiments two new ligands for D6, the CCR4 agonists CCL17 and CCL22 were identified. In summary these data suggest that CCRL2 might be involved in DC trafficking, through the regulation of the DC emigration from tissues following stimulation. None of the chemokine tested was able to bind or activate CCRL2. Furthermore CCRL2 appears not to act as a chemokine scavenger receptor and its biological role is still elusive

HIV-specific CD8 + T cells exhibit reduced and differentially regulated Cytolytic activity in Lymphoid tissue

Elimination of lymphoid tissue reservoirs is a key component of HIV eradication strategies. CD8+ T cells play a critical role in control of HIV, but their functional attributes in lymph nodes (LNs) remain unclear. Here, we show that memory, follicular CXCR5+, and HIV-specific CD8+ T cells from LNs do not manifest the properties of cytolytic CD8+ T cells. While the frequency of follicular CXCR5+ CD8+ T cells was strongly inversely associated with peripheral viremia, this association was not dependent on cytolytic CXCR5+ CD8+ T cells. Moreover, the poor cytolytic activity of LN CD8+ T cells was linked to a compartmentalized dissociation between effector programming and the transcription factor T-bet. In line with this, activation of LN CD8+ T cells only partially induced the acquisition of cytolytic functions relative to peripheral blood CD8+ T cells. These results suggest that a state of immune privilege against CD8+ T cell-mediated cytolysis exists in lymphoid tissue, potentially facilitating the persistence of HIV

The oncolytic virus dl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human solid tumor and current treatments are ineffective in increasing patients' survival. Thus, the development of new therapeutic approaches for ATC is needed. We have previously shown that the oncolytic adenovirus dl922-947 induces ATC cell death in vitro and tumor regression in vivo. However, the impact of dl922-947 on the pro-tumorigenic ATC microenvironment is still unknown. Since viruses are able to regulate cytokine and chemokine production from infected cells, we sought to investigate whether dl922-947 virotherapy has such effect on ATC cells, thereby modulating ATC microenvironment. dl922-947 decreased IL-8/CXCL8 and MCP-1/CCL2 production by the ATC cell lines 8505-c and BHT101-5. These results correlated with dl922-947-mediated reduction of NF-κB p65 binding to IL8 promoter in 8505-c and BHT101-5 cells and CCL2 promoter in 8505-c cells. IL-8 stimulates cancer cell proliferation, survival and invasion, and also angiogenesis. dl922-947-mediated reduction of IL-8 impaired ATC cell motility in vitro and ATC-induced angiogenesis in vitro and in vivo. We also show that dl922-947-mediated reduction of the monocyte-attracting chemokine CCL2 decreased monocyte chemotaxis in vitro and tumor macrophage density in vivo. Interestingly, dl922-947 treatment induced the switch of tumor macrophages toward a pro-inflammatory M1 phenotype, likely by increasing the expression of the pro-inflammatory cytokine interferon-γ. Altogether, we demonstrate that dl922-947 treatment re-shape the pro-tumorigenic ATC microenvironment by modulating cancer-cell intrinsic factors and the immune response. An in-depth knowledge of dl922-947-mediated effects on ATC microenvironment may help to refine ATC virotherapy in the context of cancer immunotherapy

Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy

Immunotherapy is a clinically validated treatment for many cancers to boost the immune system against tumor growth and dissemination. Several strategies are used to harness immune cells: monoclonal antibodies against tumor antigens, immune checkpoint inhibitors, vaccination, adoptive cell therapies (e.g., CAR-T cells) and cytokine administration. In the last decades, it is emerging that the chemokine system represents a potential target for immunotherapy. Chemokines, a large family of cytokines with chemotactic activity, and their cognate receptors are expressed by both cancer and stromal cells. Their altered expression in malignancies dictates leukocyte recruitment and activation, angiogenesis, cancer cell proliferation, and metastasis in all the stages of the disease. Here, we review first attempts to inhibit the chemokine system in cancer as a monotherapy or in combination with canonical or immuno-mediated therapies. We also provide recent findings about the role in cancer of atypical chemokine receptors that could become future targets for immunotherapy

Cell Lineage Commitment and Tumor Microenvironment as Determinants for Tumor-Associated Myelomonocytic Cells Plasticity

Ario Garza en el documento que acredita su maestría En el 81 aniversario del nacimiento de nuestro querido maestro Ario Garza Mercado, iniciamos en su honor la publicación del Blog de la Biblioteca Daniel Cosío Villegas (BDCV) de El Colegio de México (COLMEX), el cual pretende ser un canal de comunicación innovador y participativo, una ventana para que los usuarios reales y potenciales, conozcan nuestros servicios, las colecciones y también para que los Bibliotecólogos Académicos de la BDCV c..

Atypical chemokine receptors : from silence to sound

ACRs (atypical chemokine receptors) were initially referred to as 'silent' receptors on the basis of a lack of signalling and functional activities that are typically observed with conventional chemokine receptors. Although ACRs do not directly induce cell migration, they indirectly control leucocyte recruitment by shaping chemokine gradients in tissues through degradation, transcytosis or local concentration of their cognate ligands. Recent evidence also suggests that these biological activities are supported by G-protein-independent, beta-arrestin-dependent signalling events. In the present article, we review current knowledge on structural and signalling properties of ACRs that are changing our view on this entire class of receptors from silent to endogenous beta-arrestin-biased signalling receptors