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Antibiotic resistance is a major public health threat, and alternatives to antibiotic therapy are urgently needed. Immunotherapy, particularly the blockade of inhibitory immune checkpoints, is a leading treatment option in cancer and autoimmunity. In this study, we used a murine model of Salmonella Typhimurium infection to investigate whether immune checkpoint blockade could be applied to bacterial infection. We found that the immune checkpoint T-cell immunoglobulin and ITIM domain (TIGIT) was significantly upregulated on lymphocytes during infection, particularly on CD4+ T cells, drastically limiting their proinflammatory function. Blockade of TIGIT in vivo using monoclonal antibodies was able to enhance immunity and improve bacterial clearance. The efficacy of anti-TIGIT was dependent on the capacity of the antibody to bind to Fc (fragment crystallizable) receptors, giving important insights into the mechanism of anti-TIGIT therapy. This research suggests that targeting immune checkpoints, such as TIGIT, has the potential to enhance immune responses toward bacteria and restore antibacterial treatment options in the face of antibiotic resistance.
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Immunotherapy has revolutionized cancer therapy by reactivating tumour-resident cytotoxic lymphocytes. More recently, immunotherapy has emerged to restore immunity against infectious agents, including bacterial infections. Immunotherapy primarily targets inhibitory pathways in T cells, however interest in other effector populations, such as natural killer (NK) cells, is growing. We have previously discovered that NK cell metabolism, proliferation and activation can be neutralized through the immunosuppressive transforming growth factor (TGF)-ß pathway by inducing plasticity of NK cells and differentiation into innate lymphoid cell (ILC)1-like subsets. NK cells are also regulated through cytokine-inducible SH2-containing protein (CIS), which is induced by interleukin (IL)-15 and is a potent intracellular checkpoint suppressing NK cell survival and function. Targeting these two distinct pathways to restore NK cell function has shown promise in cancer models, but their application in bacterial infection remains unknown. Here, we investigate whether enhancement of NK cell function can improve anti-bacterial immunity, using Salmonella Typhimurium as a model. We identified conversion of NK cells to ILC1-like for the first time in the context of bacterial infection, where TGF-ß signalling contributed to this plasticity. Future study should focus on identifying further drivers of ILC1 plasticity and its functional implication in bacterial infection model. We further describe that CIS-deficient mice displayed enhanced pro-inflammatory function and dramatically enhanced anti-bacterial immunity. Inhibition of CIS may present as a viable therapeutic option to enhance immunity towards bacterial infection.
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Infecciones Bacterianas , Neoplasias , Animales , Inmunidad Innata , Células Asesinas Naturales , Ratones , Neoplasias/terapia , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Analysis of tumour-infiltrating T cells in colorectal cancer can predict disease-free survival. The Immunoscore, obtained by quantifying tumour-infiltrating CD3+ and CD8+ T cells, may improve current staging. Effector regulatory T cells are a potently suppressive subset in mice and, while present in human colorectal cancer, their role in patient outcome is unknown. Immunofluorescence was used to analyse immune cell infiltrates in patients with early (stage II) colorectal cancer with (n = 13) and without (n = 19) recurrent disease. CD3 and CD8 were used for the Immunoscore; FOXP3, BLIMP-1 and CD3 to identify effector regulatory T cells. Patients with high Immunoscores had increased disease-free survival compared to patients with low Immunoscores (Log-rank test p < 0.01). Prediction of outcome was further improved by stratifying patients with a low Immunoscore according to CD3+FOXP3+BLIMP-1+ cell infiltration at the invasive margin. Patients with a low Immunoscore and high infiltrate of CD3+FOXP3+BLIMP-1+ cells tended to have better disease-free survival than patients with low Immunoscore and low infiltrate of CD3+FOXP3+BLIMP-1+ cells. Patients with a high Immunoscore had better disease-free survival than patients with a low Immunoscore and low infiltrate of CD3+ FOXP3+ BLIMP-1+ cells (Log-rank test p < 0.001). These results indicate that tumour infiltration with effector regulatory T cells improves the prognostic value of the Immunoscore and implies that these cells may play a role in colorectal cancer patient outcome.
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Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/diagnóstico , Linfocitos Infiltrantes de Tumor/inmunología , Proteínas Represoras/metabolismo , Linfocitos T Reguladores/inmunología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Pruebas Inmunológicas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Nueva Zelanda , Proyectos Piloto , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Valor Predictivo de las Pruebas , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: Natural killer (NK) cells are important innate immunity players and have unique abilities to recognize and eliminate cancer cells, particularly in settings of antibody-opsonization and antibody-dependant cellular cytotoxicity (ADCC). However, NK cell-based responses in bladder cancers to therapeutic antibodies are typically immunosuppressed, and these immunosuppressive mechanisms are largely unknown. METHODS: Single cell RNA sequencing (scRNA-seq) and high-dimensional flow cytometry were used to investigate the phenotype of tumour-infiltrating NK cells in patients with bladder cancer. Further, in vitro, and in vivo models of this disease were used to validate these findings. FINDINGS: NK cells within bladder tumours displayed reduced expression of FcγRIIIa/CD16, the critical Fc receptor involved in ADCC-mediated cytotoxicity, on both transcriptional and protein levels. Transcriptional signatures of transforming growth factor (TGF)-ß-signalling, a pleiotropic cytokine known for its immunosuppressive and tissue residency-inducing effects, were upregulated in tumour-infiltrating NK cells. TGF-ß mediated CD16 downregulation on NK cells, was further validated in vitro, which was accompanied by a transition into a tissue residency phenotype. This CD16 downregulation was also abrogated by TGF-ßR signalling inhibition, which could also restore the ADCC ability of NK cells subject to TGF-ß effects. In a humanized mouse model of bladder cancer, mice treated with a TGF-ß inhibitor exhibited increased ADCC activity compared to mice treated only with antibodies. INTERPRETATION: This study highlights how TGF-ß-rich bladder cancers inhibit NK cell-mediated ADCC by downregulating CD16. TGF-ß inhibition represents new avenues to reverse immunosuppression and enhance the tumoricidal capacity of NK cells in bladder cancer. FUNDING: The Guimaraes Laboratory is funded by a US Department of Defense-Breast Cancer Research Program-Breakthrough Award Level 1 (#BC200025), a grant (#2019485) awarded through the Medical Research Future Fund (MRFF, with the support of the Queensland Children's Hospital Foundation, Microba Life Sciences, Richie's Rainbow Foundation, Translational Research Institute (TRI) and UQ), and a grant (#RSS_2023_085) funded by a Metro South Health Research Support Scheme. J.K.M.W. is funded by a UQ Research Training Program PhD Scholarship and N.O. is funded by a NHMRC Postgraduate Scholarship (#2021932).
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Células Asesinas Naturales , Receptores de IgG , Transducción de Señal , Factor de Crecimiento Transformador beta , Neoplasias de la Vejiga Urinaria , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/metabolismo , Humanos , Animales , Ratones , Factor de Crecimiento Transformador beta/metabolismo , Receptores de IgG/metabolismo , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Análisis de la Célula Individual , FemeninoRESUMEN
The emergence of multiantibiotic-resistant bacteria, often referred to as superbugs, is leading to infections that are increasingly difficult to treat. Further, bacteria have evolved mechanisms by which they subvert the immune response, meaning that even antibiotic-sensitive bacteria can persist through antibiotic therapy. For these reasons, a broad range of viable therapeutic alternatives or conjunctions to traditional antimicrobial therapy are urgently required to reduce the burden of disease threatened by antibiotic resistance. Immunotherapy has emerged as a leading treatment option in cancer, and researchers are now attempting to apply this to infectious disease. This review summarizes and discusses the recent advances in the field and highlights current and future perspectives of using immunotherapies to treat bacterial infections.
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Infecciones Bacterianas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacterias , Infecciones Bacterianas/tratamiento farmacológico , Farmacorresistencia Bacteriana , Humanos , InmunoterapiaRESUMEN
Antibodies targeting "immune checkpoints" have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8+ T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK-cell antitumor function is dependent on the cytokine IL15. Ablation of the IL15 signaling inhibitor CIS (Cish) enhances NK-cell antitumor immunity by increasing NK-cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK-cell fitness via the production of immunosuppressive transforming growth factor ß (TGFß), a suppression which occurs even in the presence of high IL15 signaling. Here, we identified an unexpected interaction between CIS and the TGFß signaling pathway in NK cells. Independently, Cish- and Tgfbr2-deficient NK cells are both hyperresponsive to IL15 and hyporesponsive to TGFß, with dramatically enhanced antitumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anticancer immunity.
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Interleucina-15 , Neoplasias , Animales , Línea Celular Tumoral , Interleucina-15/metabolismo , Células Asesinas Naturales , Ratones , Neoplasias/patología , Factor de Crecimiento Transformador beta/metabolismo , Microambiente TumoralRESUMEN
Purpose: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. Methods: We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients. Results: We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients. Conclusion: These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.
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COVID-19 , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Humanos , COVID-19/diagnóstico , COVID-19/genética , SARS-CoV-2/genética , Gripe Humana/diagnóstico , Gripe Humana/epidemiología , Gripe Humana/genética , Biomarcadores , Proteínas de la Membrana/genéticaRESUMEN
The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.