Intravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung

Intravesical administration of Bacillus Calmette-Guérin (BCG) was one of the first FDA-approved immunotherapies and remains a standard treatment for bladder cancer. Previous studies have demonstrated that intravenous (IV) administration of BCG is well-tolerated and effective in preventing tuberculosis infection in animals. Here, we examine IV BCG in several preclinical lung tumor models. Our findings demonstrate that BCG inoculation reduced tumor growth and prolonged mouse survival in models of lung melanoma metastasis and orthotopic lung adenocarcinoma. Moreover, IV BCG treatment was well-tolerated with no apparent signs of acute toxicity. Mechanistically, IV BCG induced tumor-specific CD8+ T cell responses, which were dependent on type 1 conventional dendritic cells, as well as NK cell-mediated immunity. Lastly, we also show that IV BCG has an additive effect on anti-PD-L1 checkpoint inhibitor treatment in mouse lung tumors that are otherwise resistant to anti-PD-L1 as monotherapy. Overall, our study demonstrates the potential of systemic IV BCG administration in the treatment of lung tumors, highlighting its ability to enhance immune responses and augment immune checkpoint blockade efficacy

The Bacterial Mucosal Immunotherapy MV130 Protects Against SARS-CoV-2 Infection and Improves COVID-19 Vaccines Immunogenicity

COVID-19-specific vaccines are efficient prophylactic weapons against SARS-CoV-2 virus. However, boosting innate responses may represent an innovative way to immediately fight future emerging viral infections or boost vaccines. MV130 is a mucosal immunotherapy, based on a mixture of whole heat-inactivated bacteria, that has shown clinical efficacy against recurrent viral respiratory infections. Herein, we show that the prophylactic intranasal administration of this immunotherapy confers heterologous protection against SARS-CoV-2 infection in susceptible K18-hACE2 mice. Furthermore, in C57BL/6 mice, prophylactic administration of MV130 improves the immunogenicity of two different COVID-19 vaccine formulations targeting the SARS-CoV-2 spike (S) protein, inoculated either intramuscularly or intranasally. Independently of the vaccine candidate and vaccination route used, intranasal prophylaxis with MV130 boosted S-specific responses, including CD8+-T cell activation and the production of S-specific mucosal IgA antibodies. Therefore, the bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity.CF was supported by AECC Foundation (INVES192DELF) and is currently funded by the Miguel Servet program (ID: CP20/00106) (ISCIII). IH-M receives the support of a fellowship from la Caixa Foundation (ID 100010434, fellowship code: LCF/BQ/IN17/11620074) and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 713673. AJ-C is a postgraduate fellow of the City Council of Madrid at the Residencia de Estudiantes (2020–2021). GD is supported by an European Molecular Biology Organization (EMBO) Long-term fellowship (ALTF 379-2019). This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. Project number 892965. OL and JA-C acknowledge Comunidad de Madrid (Tec4Bio-CM, S2018/NMT-4443, FEDER). Work in OL laboratory was funded by CNIO with the support of the projects Y2018/BIO4747 and P2018/NMT4443 from Comunidad de Madrid and co-funded by the European Social Fund and the European Regional Development Fund. The CNIO is supported by the Instituto de Salud Carlos III (ISCIII). Work at CNB and CISA is funded by the Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII), Fondo COVID-19 grant COV20/00151, and Fondo Supera COVID-19 (Crue Universidades-Banco Santander) (to JG-A). Work in the DS laboratory is funded by the CNIC; by the European Research Council (ERC-2016-Consolidator Grant 725091); by Agencia Estatal de Investigación (PID2019-108157RB); by Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); by Fondo Solidario Juntos (Banco Santander); by a research agreement with Inmunotek S.L.; and by Fundació La Marató de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICINN, and the Pro CNIC Foundation.Peer reviewe

Identification of new pathways involved in the regulation of the UPRmt reveals a crosstalk between mitochondrial stress response and insulin signaling

Resumen del trabajo presentado a la 21st International C. elegans Conference of the Genetics Society of America, celebrada en California, Los Angeles (US) del 21 al 25 de junio de 2017.-- et al.Depletion of the mitochondrial prohibitin complex (PHB) shows an opposite effect on aging: it shortens lifespan in wild-type worms while it dramatically extends the longevity of the already long-lived insulin/IGF-1 signaling (IIS) mutants. Moreover, PHB depletion induces a strong mitochondrial unfolded protein response (UPRmt) in wild-type animals while this response is remarkably reduced in IIS mutants. Interestingly, some of the described UPRmt components are not required for the activation of the response upon PHB depletion. We aimed at identifying new pathways involved in the regulation of the PHB-mediated mitochondrial stress response, as well as mechanisms responsible for the opposite longevity outcomes of PHB depletion. Towards this aim, we developed a semi-automated method based on double RNAi and automated image analysis to carry out RNAi screens, in PHB-depleted wild type and IIS mutants. In addition to a big number of genes involved in protein homeostasis, we describe evolutionarily conserved developmental signal transduction pathways as essential modulators of the mitochondrial stress response. Furthermore, we report pathways regulating the UPRmt in an insulin-dependent manner. Our results suggest a difference in metabolism between PHB-depleted worms and PHB-depleted;IIS mutants and place carbohydrate and lipid metabolism as possible mechanisms contributing to the opposite effect of PHB depletion in the aging phenotype of wild type and metabolically compromised animals.Peer reviewe

Genome screen identifies mechanism of Mitochondria-Insulin signalling crosstalk in the regulation of the UPRmt

Resumen del trabajo presentado al VI Spanish Worm Meeting, celebrado en Valencia del 9 al 10 de marzo de 2017.Depletion of the mitochondrial prohibitin complex (PHB) shows an opposite effect on aging: it shortens lifespan in wild-type worms while it dramatically extends the longevity of the already long-lived insulin/IGF-1 signaling (IIS) pathway mutants. Moreover, PHB depletion induces a strong mitochondrial unfolded protein response (UPRmt) in wild-type animals while this response is remarkably reduced in IIS mutants. Interestingly, some of the described UPRmt components are not required for the activation of the response upon PHB depletion. We present data from RNAi screens identifying new pathways involved in the regulation of the PHB-mediated mitochondrial stress response. In addition of transcription, protein synthesis and protein processing, we described conserved signal transduction pathways, such as MAPK signaling and TGF-ß signaling pathways, as essential modulators of the mitochondrial stress response. Furthermore we report pathways regulating the UPRmt in an insulin-dependent manner. Our results suggest a difference in metabolism between PHB-depleted worms and PHB-depleted;IIS mutants and place carbohydrate and lipid metabolism as possible mechanisms contributing to the differential effect of PHB depletion in the aging phenotype of wild-type and metabolically compromised animals.Peer reviewe