FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2893527230> ?p ?o ?g. }

• W2893527230 endingPage "3538" @default.
• W2893527230 startingPage "3528" @default.
• W2893527230 abstract "•Aerosolized antibiotic reduces lung microbiota and a tolerogenic microenvironment•Aerosol delivery of an antibiotic or probiotic decreases tumor seeding in the lung•Antibiotic or probiotic aerosol improves chemotherapy against experimental metastases Pulmonary immunological tolerance to inhaled particulates might create a permissive milieu for lung metastasis. Lung microbiota contribute to pulmonary tolerance; here, we explored whether its manipulation via antibiotic or probiotic aerosolization favors immune response against melanoma metastasis. In lungs of vancomycin/neomycin-aerosolized mice, a decrease in bacterial load was associated with reduced regulatory T cells and enhanced T cell and NK cell activation that paralleled a significant reduction of melanoma B16 lung metastases. Reduction of metastases also occurred in lungs transplanted with bacterial isolates from antibiotic-treated lungs. Aerosolized Lactobacillus rhamnosus strongly promoted immunity against B16 lung metastases as well. Furthermore, probiotics or antibiotics improved chemotherapy activity against advanced B16 metastases. Thus, we identify a role for lung microbiota in metastasis and show that its targeting via aerosolization is a therapy that can prevent metastases and enhance responses to chemotherapy. Pulmonary immunological tolerance to inhaled particulates might create a permissive milieu for lung metastasis. Lung microbiota contribute to pulmonary tolerance; here, we explored whether its manipulation via antibiotic or probiotic aerosolization favors immune response against melanoma metastasis. In lungs of vancomycin/neomycin-aerosolized mice, a decrease in bacterial load was associated with reduced regulatory T cells and enhanced T cell and NK cell activation that paralleled a significant reduction of melanoma B16 lung metastases. Reduction of metastases also occurred in lungs transplanted with bacterial isolates from antibiotic-treated lungs. Aerosolized Lactobacillus rhamnosus strongly promoted immunity against B16 lung metastases as well. Furthermore, probiotics or antibiotics improved chemotherapy activity against advanced B16 metastases. Thus, we identify a role for lung microbiota in metastasis and show that its targeting via aerosolization is a therapy that can prevent metastases and enhance responses to chemotherapy. The lung microenvironment is characterized by a high immune tolerance, which is essential for preventing excessive inflammation in response to inhaled particulates. This status is maintained by lung antigen-presenting cells (APCs), primarily alveolar macrophages (AMs) and dendritic cell (DC) subpopulations (Hussell and Bell, 2014Hussell T. Bell T.J. Alveolar macrophages: plasticity in a tissue-specific context.Nat. Rev. Immunol. 2014; 14: 81-93Crossref PubMed Scopus (800) Google Scholar), which promote immunosuppression, inducing regulatory T cells (Tregs) (Soroosh et al., 2013Soroosh P. Doherty T.A. Duan W. Mehta A.K. Choi H. Adams Y.F. Mikulski Z. Khorram N. Rosenthal P. Broide D.H. Croft M. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance.J. Exp. Med. 2013; 210: 775-788Crossref PubMed Scopus (233) Google Scholar) and the release of prostaglandin E2 (PGE2), transforming growth factor β (TGF-β), and interleukin (IL)-10 (Hussell and Bell, 2014Hussell T. Bell T.J. Alveolar macrophages: plasticity in a tissue-specific context.Nat. Rev. Immunol. 2014; 14: 81-93Crossref PubMed Scopus (800) Google Scholar). This physiological immunosuppressive status could explain the high susceptibility of the lungs to metastasis implantation from various extrapulmonary neoplasms, including melanoma, breast cancer, and colon cancer. Lung microbiota are thought not only to provide resistance to the colonization of respiratory pathogens but also to play a role in the immune tolerance of the lung microenvironment, a hypothesis supported by much evidence. In mice, increased bacterial load in the lungs and the appearance of specific bacterial taxa during the first two weeks after birth mediate the development of Tregs through the microbe-induced polarization of lung dendritic cells (Gollwitzer et al., 2014Gollwitzer E.S. Saglani S. Trompette A. Yadava K. Sherburn R. McCoy K.D. Nicod L.P. Lloyd C.M. Marsland B.J. Lung microbiota promotes tolerance to allergens in neonates via PD-L1.Nat. Med. 2014; 20: 642-647Crossref PubMed Scopus (385) Google Scholar). Moreover, the strong immune activation observed in the airways of germ-free mice sensitized and challenged intranasally with ovalbumin (OVA) is reduced after reconstitution with commensal bacteria (Herbst et al., 2011Herbst T. Sichelstiel A. Schär C. Yadava K. Bürki K. Cahenzli J. McCoy K. Marsland B.J. Harris N.L. Dysregulation of allergic airway inflammation in the absence of microbial colonization.Am. J. Respir. Crit. Care Med. 2011; 184: 198-205Crossref PubMed Scopus (319) Google Scholar). In humans, an attenuated immune response to lipopolysaccharide (LPS) stimulation was reported for AMs in the presence of a specific lung microbiota (Segal et al., 2016Segal L.N. Clemente J.C. Tsay J.C. Koralov S.B. Keller B.C. Wu B.G. Li Y. Shen N. Ghedin E. Morris A. et al.Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype.Nat. Microbiol. 2016; 1: 16031Crossref PubMed Scopus (313) Google Scholar), and the presence of Staphylococcus aureus, a lung commensal bacterium reported to polarize alveolar CD11b+ monocytes to the M2-suppressive phenotype, is essential for promoting resistance to acute inflammation induced by influenza virus (Wang et al., 2013Wang J. Li F. Sun R. Gao X. Wei H. Li L.J. Tian Z. Bacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages.Nat. Commun. 2013; 4: 2106Crossref PubMed Scopus (152) Google Scholar). Moreover, members of the Bacteroidetes phylum have been described to decrease lung inflammation (Larsen et al., 2015Larsen J.M. Musavian H.S. Butt T.M. Ingvorsen C. Thysen A.H. Brix S. Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology.Immunology. 2015; 144: 333-342Crossref PubMed Scopus (112) Google Scholar), while the lung bacteria Prevotella spp. and Veillonella spp. are associated with increased Th17 cell-mediated lung inflammation (Segal et al., 2016Segal L.N. Clemente J.C. Tsay J.C. Koralov S.B. Keller B.C. Wu B.G. Li Y. Shen N. Ghedin E. Morris A. et al.Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype.Nat. Microbiol. 2016; 1: 16031Crossref PubMed Scopus (313) Google Scholar). Furthermore, a study in HIV patients with pneumonia demonstrated that distinct lower-airway microbiota are associated with specific local host immune responses (Shenoy et al., 2017Shenoy M.K. Iwai S. Lin D.L. Worodria W. Ayakaka I. Byanyima P. Kaswabuli S. Fong S. Stone S. Chang E. et al.Immune response and mortality risk relate to distinct lung microbiomes in patients with HIV and pneumonia.Am. J. Respir. Crit. Care Med. 2017; 195: 104-114Crossref PubMed Scopus (50) Google Scholar). Nasal sprays and aerosolization are efficient and non-invasive methods to deliver molecules such as antibiotics (Zarogoulidis et al., 2013Zarogoulidis P. Kioumis I. Porpodis K. Spyratos D. Tsakiridis K. Huang H. Li Q. Turner J.F. Browning R. Hohenforst-Schmidt W. Zarogoulidis K. Clinical experimentation with aerosol antibiotics: current and future methods of administration.Drug Des. Devel. Ther. 2013; 7: 1115-1134Crossref PubMed Scopus (25) Google Scholar), antibodies (Le Noci et al., 2016Le Noci V. Sommariva M. Tortoreto M. Zaffaroni N. Campiglio M. Tagliabue E. Balsari A. Sfondrini L. Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor.OncoImmunology. 2016; 5: e1234571Crossref PubMed Scopus (28) Google Scholar), cytokines (Storti et al., 2015Storti C. Le Noci V. Sommariva M. Tagliabue E. Balsari A. Sfondrini L. Aerosol delivery in the treatment of lung cancer.Curr. Cancer Drug Targets. 2015; 15: 604-612Crossref PubMed Scopus (11) Google Scholar), Toll-like receptor agonists (Le Noci et al., 2015Le Noci V. Tortoreto M. Gulino A. Storti C. Bianchi F. Zaffaroni N. Tripodo C. Tagliabue E. Balsari A. Sfondrini L. Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment.OncoImmunology. 2015; 4: e1040214Crossref PubMed Scopus (36) Google Scholar, Sfondrini et al., 2013Sfondrini L. Sommariva M. Tortoreto M. Meini A. Piconese S. Calvaruso M. Van Rooijen N. Bonecchi R. Zaffaroni N. Colombo M.P. et al.Anti-tumor activity of CpG-ODN aerosol in mouse lung metastases.Int. J. Cancer. 2013; 133: 383-393Crossref PubMed Scopus (19) Google Scholar), and bacterial cells (Marchisio et al., 2015Marchisio P. Santagati M. Scillato M. Baggi E. Fattizzo M. Rosazza C. Stefani S. Esposito S. Principi N. Streptococcus salivarius 24SMB administered by nasal spray for the prevention of acute otitis media in otitis-prone children.Eur. J. Clin. Microbiol. Infect. Dis. 2015; 34: 2377-2383Crossref PubMed Scopus (70) Google Scholar) and therefore represent a strategy to locally modify the lung microbiota, limiting the exposure of other organs. In mice, bacterial 16S rRNA profiling revealed that the lung microbiome was efficiently modified through nasal exposure, but not oral exposure, to the antibiotic vancomycin, a glycopeptide used for inhalation in patients (ClinicalTrials.gov: NCT01509339) (Barfod et al., 2015Barfod K.K. Vrankx K. Mirsepasi-Lauridsen H.C. Hansen J.S. Hougaard K.S. Larsen S.T. Ouwenhand A.C. Krogfelt K.A. The murine lung microbiome changes during lung inflammation and intranasal vancomycin treatment.Open Microbiol. J. 2015; 9: 167-179Crossref PubMed Scopus (37) Google Scholar), and nasal administration of lactobacilli was found to stimulate respiratory immunity and to increase resistance against viral infections (Harata et al., 2010Harata G. He F. Hiruta N. Kawase M. Kubota A. Hiramatsu M. Yausi H. Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1 influenza virus infection by regulating respiratory immune responses.Lett. Appl. Microbiol. 2010; 50: 597-602Crossref PubMed Scopus (128) Google Scholar, Youn et al., 2012Youn H.N. Lee D.H. Lee Y.N. Park J.K. Yuk S.S. Yang S.Y. Lee H.J. Woo S.H. Kim H.M. Lee J.B. et al.Intranasal administration of live Lactobacillus species facilitates protection against influenza virus infection in mice.Antiviral Res. 2012; 93: 138-143Crossref PubMed Scopus (80) Google Scholar). In humans, inhaled antibiotics are used to treat critical lung infections (Geller, 2009Geller D.E. Aerosol antibiotics in cystic fibrosis.Respir. Care. 2009; 54: 658-670Crossref PubMed Scopus (138) Google Scholar), while the administration of Streptococcus salivarius by nasal spray has been reported to prevent acute otitis in children (Marchisio et al., 2015Marchisio P. Santagati M. Scillato M. Baggi E. Fattizzo M. Rosazza C. Stefani S. Esposito S. Principi N. Streptococcus salivarius 24SMB administered by nasal spray for the prevention of acute otitis media in otitis-prone children.Eur. J. Clin. Microbiol. Infect. Dis. 2015; 34: 2377-2383Crossref PubMed Scopus (70) Google Scholar). To our knowledge, no studies aiming to alter the pulmonary microbiota, to subvert the immune-suppressive lung microenvironment and to establish local immunity against cancer, have been performed. In this study, we evaluated whether the nebulization of antibiotics or probiotics to modify the lung microbiota results in immunosurveillance against lung cancer metastases. To evaluate whether a reduction of the lung microbiota mitigates the immunosuppressive status in the lung microenvironment, mice were treated with broad-spectrum antibiotics by airway delivery. Specifically, mice were aerosolized with both vancomycin, which is directed to Gram-positive bacteria, and neomycin, which acts against several Gram-negative bacteria and partially against Gram-positive bacteria, or with saline for 5 days. The commensal bacterial load decreased in the bronchoalveolar lavage (BAL) of antibiotic-treated mice (mean colony-forming unit [CFU]/mL: 313.3 ± 173.7 in antibiotic-treated mice versus 1,390 ± 152.4 in saline-treated mice, p = 0.0056) (Figure 1A). Fluorescence-activated cell sorting (FACS) analysis of digested lung suspensions revealed that the decrease in bacterial load induced by antibiotic aerosolization did not significantly change the percentage of T cells, natural killer (NK) cells, DCs, and AMs infiltrating the lungs (Figure S1). Conversely, it resulted in a reduction of the percentage of the tolerogenic population of CD4+CD25+FoxP3+ Tregs (Figure 1B). This reduction was associated with a drop in IL-2 level in BAL, a factor essential for expansion and survival of Tregs, suggesting that the decline of Tregs might be related to a reduced bioavailability of IL-2 in the lung microenvironment (Figure 1C). A diminished fraction of proliferating Tregs, defined by the expression of the Ki-67 proliferation marker, was observed in antibiotic-treated lungs (Figure 1D), while no difference in CCR4 expression (Figure 1E), a chemokine receptor involved in migration of Treg, was detected. A decrease of IL-10-producing Tregs, a cytokine implicated in their functional activity, was also observed ex vivo in lung suspensions from antibiotic-treated mice (Figure 1F). The effects of antibiotic treatment on the implantation of tumor cells in the lungs were evaluated in mice pre-treated with aerosolized antibiotics or saline for 2 weeks, intravenously (i.v.) injected with B16 melanoma cells, and treated again with antibiotics for another 3 weeks. At the end of the treatment, the number of macroscopic melanotic metastases was significantly reduced in antibiotic- versus saline-treated mice (p < 0.0001) (Figure 2A). No overt signs of toxicity, such as weight loss, hunching, ruffled fur, or difficulty breathing, were observed in mice treated with antibiotics (Figure S2A). Histopathological examination of the lung tissues showed the absence of injury in the lung parenchyma (Figure S2C). To examine the effect of each antibiotic, the experiment was repeated by treating the mice with vancomycin or neomycin alone or their combination. A reduction in the number of B16 lung metastases was observed in both the vancomycin- and the neomycin-treated groups, even if a significant decrease compared to the saline-treated mice was achieved only in the combination group (p = 0.395 in vancomycin-treated mice, p = 0.053 in neomycin-treated mice, and p = 0.0464 in vancomycin- and neomycin-treated mice versus saline-treated mice) (Figure 2B). FACS analysis of lung cell suspensions obtained from mice i.v. injected with tumor cells and aerosolized with vancomycin and neomycin or saline revealed no modulation of Tregs (Figure 2C), but a significant reduction of IL-10-producing Tregs was found in antibiotic-treated mice (Figure 2D). No difference in the percentage and a strong upregulation of CD69 were observed in T cells (Figures 2E and 2F), whereas both increased recruitment and a strong upregulation of CD69 were detectable in NK cells (Figures 2E and 2F). The increased recruitment and activation of NK cells were associated with increased cytotoxic activity evaluated in vitro against NK-sensitive YAC target cells (Figure 2G). These results indicate that local antibiotic treatment reduces the implantation of experimental lung metastases and that this effect is associated with a modulation of the immune response. 16S rRNA gene profiling revealed that 5-day administration of vancomycin and neomycin via aerosol significantly increased (α) diversity in terms of bacterial richness, estimated by the number of observed operational taxonomic units (OTUs) and the Chao1 index. On the contrary, no difference was observed with indexes that estimate biodiversity while considering bacterial evenness (i.e., Shannon, Simpson, and inverse Simpson). At the taxonomic level, antibiotic treatment modified BAL microbiota, drastically reducing the population of the genus Streptococcus, which are common Gram-positive Firmicutes commensal of the respiratory tract; concomitantly, antibiotic administration led to the expansion in BAL microbiota of the generally less represented genera of the Gram-negative phylum Proteobacteria. In addition, we found expansion of members of the Gram-positive phylum Actinobacteria (Figure S3). To assess the effect of bacteria expanded upon antibiotic treatment on metastasis growth, we treated or did not treat mice with vancomycin and neomycin as done previously and isolated bacterial strains from the BAL. According to the colony morphology, from the BAL of antibiotic-treated mice, we isolated two bacterial strains that were taxonomically assigned to the Gram-negative Proteobacteria taxa (Morganella morganii and Escherichia fergusonii) (Figure 3A). In contrast, the three strains isolated from the BAL of the untreated mice were taxonomically identified as Gram-positive Firmicutes species (two morphologically and genetically different isolates of Paenibacillus glucanolyticus and Bacillus clausii) (Figure 3A). To determine the effects of commensal bacteria isolated from antibiotic-treated or untreated lungs on metastasis growth, a transfer experiment was performed. Specifically, a group of mice was aerosolized for 3 weeks with a bacterial cells suspension of the two strains isolated from the BAL of mice treated with vancomycin and neomycin aerosol (group G2), while another group was aerosolized with saline (group G1). Conversely, to assess whether the strains isolated from the untreated lungs were able to reverse the antitumor effect of antibiotic treatment, the third and fourth groups of mice were treated by 5-day aerosolization with vancomycin and neomycin to reduce their commensal flora and then aerosolized with a combination of the three bacterial strains isolated from untreated mice (group G4), to re-colonize their lungs, or with saline (group G3). All groups were i.v. injected with B16 melanoma cells 24 hr after the first bacterial or saline aerosolization, and the number of lung metastases was counted 3 weeks later. A significant reduction in the number of metastases was observed in the group aerosolized with bacteria isolated from antibiotic-treated lungs (group G2) versus that from the saline-treated group (group G1) (p = 0.0005) (Figure 3B). Moreover, as shown in the figure, antibiotic aerosol treatment, even when limited to the 5 days before tumor injection, significantly reduced the implantation of lung metastases (group G3), but re-colonization of antibiotic-treated mice by aerosolization of commensal bacteria isolated from the lungs of untreated mice (group G4) attenuated the protective effect of antibiotic treatment compared to saline-treated mice (Figure 3B). These results exclude a direct effect of the antibiotics on tumor implantation and growth and indicate that resident bacteria control tumor implantation in the lung by influencing the immune landscape of the lung tissue. Our data indicate that aerosolization of bacteria isolated from lung microbiota of antibiotic-treated mice reduces lung metastasis implantation. Thus, because these bacteria include opportunistic pathogen species that typically arise after antibiotic treatment, we evaluated whether the immunosuppressive effects of the resident microflora can be overcome by the aerosolization of safe bacteria with immunostimulatory properties such as Lactobacillus rhamnosus GG, which reportedly enhances cell-mediated immunity by intranasal administration in viral infection models (Harata et al., 2010Harata G. He F. Hiruta N. Kawase M. Kubota A. Hiramatsu M. Yausi H. Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1 influenza virus infection by regulating respiratory immune responses.Lett. Appl. Microbiol. 2010; 50: 597-602Crossref PubMed Scopus (128) Google Scholar, Youn et al., 2012Youn H.N. Lee D.H. Lee Y.N. Park J.K. Yuk S.S. Yang S.Y. Lee H.J. Woo S.H. Kim H.M. Lee J.B. et al.Intranasal administration of live Lactobacillus species facilitates protection against influenza virus infection in mice.Antiviral Res. 2012; 93: 138-143Crossref PubMed Scopus (80) Google Scholar). Aerosolized L. rhamnosus GG reached the lung in a viable form (Figure S4) and significantly reduced the number of lung metastases compared to saline treatment when aerosolized for 2 weeks before B16 melanoma cells were i.v. injected and for the 3 weeks before sacrifice (Figure 4A). No weight loss or other signs of toxicity and no injury to the lung parenchyma were observed (Figures S2B and S2C). Numerous reports have shown that Lactobacillus spp. may mediate anticancer effects through DC maturation (Mohamadzadeh et al., 2005Mohamadzadeh M. Olson S. Kalina W.V. Ruthel G. Demmin G.L. Warfield K.L. Bavari S. Klaenhammer T.R. Lactobacilli activate human dendritic cells that skew T cells toward T helper 1 polarization.Proc. Natl. Acad. Sci. USA. 2005; 102: 2880-2885Crossref PubMed Scopus (376) Google Scholar). In agreement, as shown in Figures 4B and 4C, analysis of lung suspensions from mice i.v. injected with B16 tumor cells and aerosolized with L. rhamnosus revealed that this treatment enhanced the maturation of AMs and of CD103+ DCs and CD11b+ DCs, the two major DC populations residing in the lung that are involved in migration to the lymph nodes for tumor-derived antigen presentation (Sung et al., 2006Sung S.S. Fu S.M. Rose Jr., C.E. Gaskin F. Ju S.T. Beaty S.R. A major lung CD103 (alphaE)-beta7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins.J. Immunol. 2006; 176: 2161-2172Crossref PubMed Scopus (390) Google Scholar); however, no increase was detected in the percentage of these three populations (data not shown). Specifically, the expression of CD80 and CD86 maturation markers on CD103+ DCs was significantly upregulated, CD11b+ DCs displayed higher positivity for major histocompatibility complex class II (MHC class II) molecules, and there was a trend suggesting the upmodulation of CD80 and CD86 (Figures 4B and 4C). Moreover, L. rhamnosus significantly upregulated CD80 on AMs (Figures 4B and 4C). The increased maturation of CD103+ DCs and AMs following the aerosolization of L. rhamnosus was also observed in the lungs of tumor-free FVB mice (data not shown), indicating that the maturation of resident APCs by L. rhamnosus increased in the absence of tumor cells and that this effect was not restricted to the specific reactivity of APCs in C57BL/6 mice. Moreover, the maturation of resident APCs was associated with reduced expression of M2 genes, as revealed by real-time PCR analysis performed on mRNA extracted from the adherent cell fraction of digested lungs that contains macrophages and myeloid cells. M2-related genes, such as Il10, Ido, and Irf4, significantly declined in adherent cells from the lungs of L. rhamnosus-aerosolized mice versus untreated mice (Figure 5). Moreover, there was a trend suggesting a reduction in TGF-β and PGE2 expression. In contrast, M1 markers, such as IL-12 and IRF5, were significantly upregulated (Figure 5). In contrast to that observed in antibiotic-treated lungs, no significant reduction in the percentage of Treg was observed in lung suspensions obtained from L. rhamnosus-treated mice (mean ± SEM of the percentage of CD25+FoxP3+ cells in the CD45+CD3+CD4+ fraction: 9.8 ± 0.8 in probiotic-treated mice versus 11.2 ± 0.7 in saline-treated mice). No differences were observed in the recruitment of NK cells or T cells in the lungs of tumor-bearing mice between the two groups of mice (data not shown). However, the increased expression of maturation markers on APCs in B16 tumor-bearing lung suspensions from mice aerosolized with L. rhamnosus was associated with the enhanced expression of CD69 on both T and NK populations and with increased levels of the activatory NK receptor NKG2D (Figure 6). Depletion experiments confirmed the role of NK cells in the antitumor effects of L. rhamnosus in the low immunogenic NK-sensitive B16 tumor model (Figure S5). However, we cannot exclude that L. rhamnosus might also promote T cell-mediated cytotoxic activity against immunogenic tumors. These results suggest that aerosolized L. rhamnosus promotes the maturation of resident APCs in the lungs and reduces the M2 microenvironment, resulting in the increased activation of effector cells. In addition to lactobacilli, Bifidobacterium is the probiotic genus most frequently investigated for its immunomodulatory properties (Vlasova et al., 2016Vlasova A.N. Kandasamy S. Chattha K.S. Rajashekara G. Saif L.J. Comparison of probiotic lactobacilli and bifidobacteria effects, immune responses and rotavirus vaccines and infection in different host species.Vet. Immunol. Immunopathol. 2016; 172: 72-84Crossref PubMed Scopus (98) Google Scholar). In particular, the species B. bifidum, which exclusively colonizes the healthy human colon (Turroni et al., 2014Turroni F. Duranti S. Bottacini F. Guglielmetti S. Van Sinderen D. Ventura M. Bifidobacterium bifidum as an example of a specialized human gut commensal.Front. Microbiol. 2014; 5: 437Crossref PubMed Scopus (79) Google Scholar), has been demonstrated to stimulate DC to acquire Th1 stimulatory capacity (Guglielmetti et al., 2014Guglielmetti S. Zanoni I. Balzaretti S. Miriani M. Taverniti V. De Noni I. Presti I. Stuknyte M. Scarafoni A. Arioli S. et al.Murein lytic enzyme TgaA of Bifidobacterium bifidum MIMBb75 modulates dendritic cell maturation through its cysteine- and histidine-dependent amidohydrolase/peptidase (CHAP) amidase domain.Appl. Environ. Microbiol. 2014; 80: 5170-5177Crossref PubMed Scopus (26) Google Scholar). Thus, after establishing its ability to significantly mature resident APCs in the lungs when administered by aerosol (data not shown), the strain B. bifidum MIMBb23sg was applied, and its effects were compared to those of L. rhamnosus in subsequent experiments. To investigate whether aerosolization with probiotics boosts the immune response against a growing tumor after its implantation in the lung, we evaluated the efficacy of aerosolized lactobacilli in a therapeutic protocol by initiating aerosolization 7 days after tumor injection, when metastatic foci are detectable in the lungs (Le Noci et al., 2016Le Noci V. Sommariva M. Tortoreto M. Zaffaroni N. Campiglio M. Tagliabue E. Balsari A. Sfondrini L. Reprogramming the lung microenvironment by inhaled immunotherapy fosters immune destruction of tumor.OncoImmunology. 2016; 5: e1234571Crossref PubMed Scopus (28) Google Scholar). This treatment was combined with dacarbazine (DTIC), a conventional chemotherapeutic agent used in metastatic melanoma patients that exerts immunostimulatory effects (Hervieu et al., 2013Hervieu A. Rébé C. Végran F. Chalmin F. Bruchard M. Vabres P. Apetoh L. Ghiringhelli F. Mignot G. Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth.J. Invest. Dermatol. 2013; 133: 499-508Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). The mice were i.v. injected with B16 melanoma cells and treated from day 7 to day 21 with DTIC alone or in combination with aerosolized L. rhamnosus or B. bifidum. Two other groups of mice received L. rhamnosus or B. bifidum alone, and one group was left untreated. The antitumor effect of DTIC was significantly increased when combined with L. rhamnosus or B. bifidum (Figure 7A) with a comparable improvement, but no significant effect was observed following treatment with each probiotic alone. FACS analysis of cell suspensions obtained from mice i.v. injected with tumor cells and then aerosolized with L. rhamnosus revealed no differences in the recruitment of NK cells or T cells (data not shown); nonetheless, a significant increased CD69 expression was observed in both NK and T cells in DTIC and probiotic- versus DTIC-treated mice (Figure 7B). This increased activation of effector cells was associated with a higher ability to lyse B16 tumor cells (Figure 7C). Because the preceding experiments revealed that a reduction in the commensal lung microbiota promoted immune activation, we next evaluated whether aerosolization with antibiotics improved the antitumor efficacy of DTIC in the therapeutic protocol. A significant increase in the antitumor effect of DTIC was observed in mice i.v. injected with B16 melanoma cells and treated as described previously from day 7 to day 21 with the chemotherapeutic drug and aerosolized vancomycin and neomycin (Figure 7D). Increased cytotoxic activity was observed against B16 target cells in lung suspensions from mice treated with DTIC and vancomycin and neomycin compared to those from mice treated with DTIC alone (Figure 7E). These results suggest that the local administration of immunostimulatory probiotics or the reduction of immunosuppressive commensal species by antibiotics improves the antitumor effect of DTIC. In this proof-of-concept study, we demonstrate that the commensal lung microbiota are manipulated by antibiotic or probiotic aerosolization and that changes induced by these treatments are associated with a reduction in the immune suppression present in the lung microenvironment, thus favoring an immune response against cancer cells. Antibiotic aerosolization is a compelling strategy used to achieve high antibiotic concentrations in the airway to maximize bacterial killing with minimal systemic side effects (Zarogoulidis et al., 2013Zarogoulidis P. Kioumis I. Porpodis K. Spyratos D. Tsakiridis K." @default.
• W2893527230 created "2018-10-05" @default.
• W2893527230 creator A5017651486 @default.
• W2893527230 creator A5027514716 @default.
• W2893527230 creator A5046737386 @default.
• W2893527230 creator A5047659823 @default.
• W2893527230 creator A5059818282 @default.
• W2893527230 creator A5067882748 @default.
• W2893527230 creator A5077503045 @default.
• W2893527230 creator A5077890463 @default.
• W2893527230 creator A5083469846 @default.
• W2893527230 creator A5088321927 @default.
• W2893527230 creator A5089066322 @default.
• W2893527230 creator A5090248620 @default.
• W2893527230 date "2018-09-01" @default.
• W2893527230 modified "2023-10-16" @default.
• W2893527230 title "Modulation of Pulmonary Microbiota by Antibiotic or Probiotic Aerosol Therapy: A Strategy to Promote Immunosurveillance against Lung Metastases" @default.
• W2893527230 cites W1266271947 @default.
• W2893527230 cites W1482002974 @default.
• W2893527230 cites W1797078024 @default.
• W2893527230 cites W1941372961 @default.
• W2893527230 cites W1950729478 @default.
• W2893527230 cites W1962126510 @default.
• W2893527230 cites W1979794707 @default.
• W2893527230 cites W1997990116 @default.
• W2893527230 cites W1999615949 @default.
• W2893527230 cites W2013836431 @default.
• W2893527230 cites W2021310231 @default.
• W2893527230 cites W2023689593 @default.
• W2893527230 cites W2031784540 @default.
• W2893527230 cites W2035033855 @default.
• W2893527230 cites W2043066292 @default.
• W2893527230 cites W2047902191 @default.
• W2893527230 cites W2063188234 @default.
• W2893527230 cites W2067806364 @default.
• W2893527230 cites W2068521142 @default.
• W2893527230 cites W2097808005 @default.
• W2893527230 cites W2102455033 @default.
• W2893527230 cites W2102923323 @default.
• W2893527230 cites W2111740348 @default.
• W2893527230 cites W2118666817 @default.
• W2893527230 cites W2120579640 @default.
• W2893527230 cites W2123895022 @default.
• W2893527230 cites W2124721975 @default.
• W2893527230 cites W2145720531 @default.
• W2893527230 cites W2146068800 @default.
• W2893527230 cites W2146799440 @default.
• W2893527230 cites W2161870183 @default.
• W2893527230 cites W2166820811 @default.
• W2893527230 cites W2278665679 @default.
• W2893527230 cites W2287681468 @default.
• W2893527230 cites W2343030398 @default.
• W2893527230 cites W2473042277 @default.
• W2893527230 cites W2505233376 @default.
• W2893527230 cites W2521491845 @default.
• W2893527230 cites W2571277016 @default.
• W2893527230 cites W2790589159 @default.
• W2893527230 doi "https://doi.org/10.1016/j.celrep.2018.08.090" @default.
• W2893527230 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30257213" @default.
• W2893527230 hasPublicationYear "2018" @default.
• W2893527230 type Work @default.
• W2893527230 sameAs 2893527230 @default.
• W2893527230 citedByCount "123" @default.
• W2893527230 countsByYear W28935272302018 @default.
• W2893527230 countsByYear W28935272302019 @default.
• W2893527230 countsByYear W28935272302020 @default.
• W2893527230 countsByYear W28935272302021 @default.
• W2893527230 countsByYear W28935272302022 @default.
• W2893527230 countsByYear W28935272302023 @default.
• W2893527230 crossrefType "journal-article" @default.
• W2893527230 hasAuthorship W2893527230A5017651486 @default.
• W2893527230 hasAuthorship W2893527230A5027514716 @default.
• W2893527230 hasAuthorship W2893527230A5046737386 @default.
• W2893527230 hasAuthorship W2893527230A5047659823 @default.
• W2893527230 hasAuthorship W2893527230A5059818282 @default.
• W2893527230 hasAuthorship W2893527230A5067882748 @default.
• W2893527230 hasAuthorship W2893527230A5077503045 @default.
• W2893527230 hasAuthorship W2893527230A5077890463 @default.
• W2893527230 hasAuthorship W2893527230A5083469846 @default.
• W2893527230 hasAuthorship W2893527230A5088321927 @default.
• W2893527230 hasAuthorship W2893527230A5089066322 @default.
• W2893527230 hasAuthorship W2893527230A5090248620 @default.
• W2893527230 hasBestOaLocation W28935272301 @default.
• W2893527230 hasConcept C126322002 @default.
• W2893527230 hasConcept C203014093 @default.
• W2893527230 hasConcept C2776885095 @default.
• W2893527230 hasConcept C2777714996 @default.
• W2893527230 hasConcept C2780255968 @default.
• W2893527230 hasConcept C2993328841 @default.
• W2893527230 hasConcept C501593827 @default.
• W2893527230 hasConcept C523546767 @default.
• W2893527230 hasConcept C54355233 @default.
• W2893527230 hasConcept C71924100 @default.
• W2893527230 hasConcept C86803240 @default.
• W2893527230 hasConcept C8891405 @default.
• W2893527230 hasConcept C89423630 @default.
• W2893527230 hasConceptScore W2893527230C126322002 @default.
• W2893527230 hasConceptScore W2893527230C203014093 @default.

• next