Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer

Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases. Findings from bronchoalveolar lavage might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify patients with non–small cell lung cancer (NSCLC) who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis of 12 patients were compared with regard to therapeutic effect. Compared with ICI nonresponders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti–PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and the balance of CXCL9 and lung TME microbiome could contribute to nivolumab sensitivity in patients with NSCLC. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.

[1]  A. Flügel,et al.  The lung microbiome regulates brain autoimmunity , 2022, Nature.

[2]  Bowen Diao,et al.  Comprehensive Analysis of the Expression and Prognosis for Laminin Genes in Ovarian Cancer , 2021, Pathology & Oncology Research.

[3]  T. Aoshi,et al.  Microfluidics sorting enables the isolation of an intact cellular pair complex of CD8+ T cells and antigen-presenting cells in a cognate antigen recognition-dependent manner , 2021, PloS one.

[4]  John G Doench,et al.  CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor cells and T cells. , 2021, Cancer discovery.

[5]  P. Van Loo,et al.  Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition , 2021, Cell.

[6]  Richard Bonneau,et al.  Lower airway dysbiosis affects lung cancer progression. , 2020, Cancer discovery.

[7]  T. Greiling,et al.  Host–microbiota interactions in immune-mediated diseases , 2020, Nature Reviews Microbiology.

[8]  M. Vasson,et al.  Characterisation of microbiota in saliva, bronchoalveolar lavage fluid, non-malignant, peritumoural and tumour tissue in non-small cell lung cancer patients: a cross-sectional clinical trial , 2020, Respiratory Research.

[9]  D. Isla,et al.  The Influence of Lung Microbiota on Lung Carcinogenesis, Immunity, and Immunotherapy. , 2020, Trends in cancer.

[10]  Rongchang Chen,et al.  A Refined View of Airway Microbiome in Chronic Obstructive Pulmonary Disease at Species and Strain-Levels , 2020, bioRxiv.

[11]  K. Ishii,et al.  Antigen-specific Mucosal Immunity Regulates Development of Intestinal Bacteria-mediated Diseases. , 2019, Gastroenterology.

[12]  S. Loi,et al.  Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade , 2019, Clinical Cancer Research.

[13]  A. Drilon,et al.  Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[14]  J. Emile,et al.  Role of antibiotic use, plasma citrulline and blood microbiome in advanced non-small cell lung cancer patients treated with nivolumab , 2019, Journal of Immunotherapy for Cancer.

[15]  D. Ito,et al.  Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells. , 2018, JCI insight.

[16]  Fan Zhang,et al.  Fast, sensitive, and accurate integration of single cell data with Harmony , 2018, bioRxiv.

[17]  Richard Bonneau,et al.  Airway Microbiota Is Associated with Upregulation of the PI3K Pathway in Lung Cancer , 2018, American journal of respiratory and critical care medicine.

[18]  Eric C. Polley,et al.  Interaction between the microbiome and TP53 in human lung cancer , 2018, Genome Biology.

[19]  Kaushal Parikh,et al.  Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors , 2018, Oncoimmunology.

[20]  J. Erb-Downward,et al.  The Lung Microbiota of Healthy Mice Are Highly Variable, Cluster by Environment, and Reflect Variation in Baseline Lung Innate Immunity , 2018, American journal of respiratory and critical care medicine.

[21]  L. Zitvogel,et al.  Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[22]  Mark D. Robinson,et al.  Compensation of Signal Spillover in Suspension and Imaging Mass Cytometry , 2018, Cell systems.

[23]  J. Wargo,et al.  The gut microbiota influences anticancer immunosurveillance and general health , 2018, Nature Reviews Clinical Oncology.

[24]  R. Greil,et al.  Impact of antibiotic treatment on immune-checkpoint blockade efficacy in advanced non-squamous non-small cell lung cancer , 2018, Oncotarget.

[25]  J. Tosello,et al.  Tumor Necrosis Factor α and Regulatory T Cells in Oncoimmunology , 2018, Front. Immunol..

[26]  Jing Zhang,et al.  Difference of lower airway microbiome in bilateral protected specimen brush between lung cancer patients with unilateral lobar masses and control subjects , 2018, International journal of cancer.

[27]  Laurence Zitvogel,et al.  Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors , 2018, Science.

[28]  E. Le Chatelier,et al.  Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients , 2018, Science.

[29]  Riyue Bao,et al.  The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients , 2018, Science.

[30]  J. Horton,et al.  A Phase II Study of Pembrolizumab in EGFR‐Mutant, PD‐L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[31]  C. Niu,et al.  Prognostic value of MICA/B in cancers: a systematic review and meta-analysis , 2017, Oncotarget.

[32]  G. Freeman,et al.  Interleukin‐17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD‐1 Blockade , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[33]  S. Uematsu,et al.  Intestinal microbiota link lymphopenia to murine autoimmunity via PD-1+CXCR5−/dim B-helper T cell induction , 2017, Scientific Reports.

[34]  Jeffrey L. Curtis,et al.  Bacterial Topography of the Healthy Human Lower Respiratory Tract , 2017, mBio.

[35]  M. Atkins,et al.  Predictive biomarkers for checkpoint inhibitor-based immunotherapy. , 2016, The Lancet. Oncology.

[36]  J. Chun,et al.  Characterization of microbiome in bronchoalveolar lavage fluid of patients with lung cancer comparing with benign mass like lesions. , 2016, Lung cancer.

[37]  Hao Chen,et al.  Cytofkit: A Bioconductor Package for an Integrated Mass Cytometry Data Analysis Pipeline , 2016, PLoS Comput. Biol..

[38]  John C Marioni,et al.  A step-by-step workflow for low-level analysis of single-cell RNA-seq data with Bioconductor , 2016, F1000Research.

[39]  Paul J. McMurdie,et al.  DADA2: High resolution sample inference from Illumina amplicon data , 2016, Nature Methods.

[40]  I. Melero,et al.  Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs) , 2016, Clinical Cancer Research.

[41]  H. Maecker,et al.  Platinum‐conjugated antibodies for application in mass cytometry , 2016, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[42]  F. Martinez,et al.  The Microbiome and the Respiratory Tract. , 2016, Annual review of physiology.

[43]  Jason B. Williams,et al.  Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy , 2015, Science.

[44]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[45]  C. Rudin,et al.  Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[46]  Xinmin Yan,et al.  Discovery and validation of potential bacterial biomarkers for lung cancer. , 2015, American journal of cancer research.

[47]  J. Yewdell,et al.  CXCR3 chemokine receptor enables local CD8(+) T cell migration for the destruction of virus-infected cells. , 2015, Immunity.

[48]  B. Marsland,et al.  Host–microorganism interactions in lung diseases , 2014, Nature Reviews Immunology.

[49]  T. Yen,et al.  IL-6-stimulated CD11b+CD14+HLA-DR− myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus , 2014, Oncotarget.

[50]  M. Cheng,et al.  Microbiota modulate tumoral immune surveillance in lung through a γδT17 immune cell-dependent mechanism. , 2014, Cancer research.

[51]  Jae-Hun Kim,et al.  Improvement of orthotopic lung cancer mouse model via thoracotomy and orotracheal intubation enabling in vivo imaging studies , 2014, Laboratory animals.

[52]  A. Fields,et al.  Utility and Applications of Orthotopic Models of Human Non‐Small Cell Lung Cancer (NSCLC) for the Evaluation of Novel and Emerging Cancer Therapeutics , 2013, Current protocols in pharmacology.

[53]  J. Egen,et al.  Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node. , 2013, Immunity.

[54]  U. V. von Andrian,et al.  CXCR3 chemokine receptor-ligand interactions in the lymph node optimize CD4+ T helper 1 cell differentiation. , 2012, Immunity.

[55]  Kyle Bittinger,et al.  Topographical continuity of bacterial populations in the healthy human respiratory tract. , 2011, American journal of respiratory and critical care medicine.

[56]  G. Stathopoulos,et al.  Granulocyte colony-stimulating factor expression as a prognostic biomarker in non-small cell lung cancer. , 2011, Oncology reports.

[57]  T. Aoshi,et al.  Expression mapping using a retroviral vector for CD8+ T cell epitopes: definition of a Mycobacterium tuberculosis peptide presented by H2-Dd. , 2005, Journal of immunological methods.

[58]  C. Galanos,et al.  Cutting Edge: A Murine, IL-12-Independent Pathway of IFN-γ Induction by Gram-Negative Bacteria Based on STAT4 Activation by Type I IFN and IL-18 Signaling1 , 2002, The Journal of Immunology.

[59]  J. Finke,et al.  The CXC chemokines IP-10 and Mig are necessary for IL-12-mediated regression of the mouse RENCA tumor. , 1998, Journal of immunology.

[60]  J. Farber.  Mig and IP‐10: CXC chemokines that target lymphocytes , 1997, Journal of leukocyte biology.

[61]  Y. Ohmori,et al.  Tumor necrosis factor-alpha induces cell type and tissue-specific expression of chemoattractant cytokines in vivo. , 1993, The American journal of pathology.

[62]  J. Lunceford,et al.  IFN- γ –related mRNA profile predicts clinical response to PD-1 blockade , 2017 .

[63]  A. Didier,et al.  [Incidence and characteristics of bronchial colonisation in patient with lung cancer: a retrospective study of 388 cases]. , 2011, Revue des maladies respiratoires.