Molecular characterization of Kita-Kyushu lung cancer antigen (KK-LC-1) expressing carcinomas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21000-e21000
Author(s):  
Robert Hsu ◽  
Yasmine Baca ◽  
Joanne Xiu ◽  
Rongfu Wang ◽  
Joseph Nicholas Bodor ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Cell ◽  
Molecular Subtype ◽  
Statistical Significance ◽  
Cell Receptor ◽  
Wild Type ◽  
Chi Square ◽  
Lung Cancers ◽  
Genome Medicine ◽  
M1 Macrophage

e21000 Background: Cancer/testis antigens (CTAs) are strongly expressed in some solid tumors but minimally expressed in normal tissue, making them appealing therapeutic targets. KK-LC-1 (CXorf61) has cytoplasmic expression in some types of gastric and breast cancer and reports of expression in one-third of lung cancer tumors. Here, we characterize the molecular subtype of lung cancers expressing KK-LC-1 to plan rational clinical trials of T-cell receptor therapy (TCR-T) targeting KK-LC-1. Methods: A total of 9790 non-small cell lung cancer (NSCLC) tumors that underwent whole transcriptome sequencing (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ) were analyzed. Tumors were split into quartiles based on KK-LC-1 expression and pathological and molecular differences were investigated. PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported. Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Statistical significance was determined using chi-square/Fisher-Exact and adjusted for multiple comparisons (adjusted p < 0.05). Results: Adenocarcinoma had significantly higher KK-LC-1 expression than squamous cell carcinoma (median 3.25 vs. 1.17 transcripts per million (TPM), p < 0.0001). There is statistically higher expression of KK-LC-1 in pan wild type (3.95 TPM) compared to tumors with EGFR mutation (1.95 TPM), ALK fusion (0.6 TPM), MET exon-14-skip mutation (1.22 TPM), RET fusion (1.42 TPM), and ROS1 fusion (1.78 TPM). Tumors within the highest quartile of KK-LC-1 expression (Q4) had a greater proportion of TMB > 10 mutations per megabase (mt/MB) (44% vs. 28%) compared to Q1. No difference was seen in PD-L1 expression. In adenocarcinoma, Q4 had a higher TMB compared to Q1 (9 mt/MB vs. 5 mt/MB). There was a higher KRAS mutation prevalence in Q3/Q4 (34.8%/35.0%) than Q1/Q2 (22%/29%) but a lower ALK fusion prevalence in Q3/Q4 (1.0%/0.5%) compared to Q1/Q2 (3.3%/2.6%). Increased KK-LC-1 expression is associated with increased M1 Macrophage abundance. Conclusions: In our population, KK-LC-1 expression was higher in adenocarcinoma. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with higher TMB while lower levels of expression were seen in driver positive cancers including EGFR, ALK, MET, RET and ROS1. TCR-T therapy directed against KK-LC-1 should be explored in patients whose clinical features reflect these characteristics.

scholarly journals The BRCA2 mutation status shapes the immune phenotype of prostate cancer

2019 ◽  
Vol 68 (10) ◽  
pp. 1621-1633 ◽  
Author(s):  
Maximilian Jenzer ◽  
Peter Keß ◽  
Cathleen Nientiedt ◽  
Volker Endris ◽  
Maximilian Kippenberger ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Statistical Significance ◽  
Brca2 Mutation ◽  
Cell Receptor ◽  
Wild Type ◽  
Immune Phenotype ◽  
Damage Repair

Abstract Defects in DNA damage repair caused by mutations in BRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation between BRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eight BRCA2-mutated tumors in comparison with eight BRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyzed seven prostate cancer biopsies that were either BRCA2 or ATM-mutated in comparison with wild-type tumors. Whereas in BRCA1/2 wild-type tumors, immune cells were found predominantly extratumorally, most BRCA2-mutated tumors including one biopsy showed a significantly increased intratumoral immune cell infiltration. The ratio of intratumoral to extratumoral immune cells was considerably higher in BRCA2-mutated tumors for all markers and reached statistical significance for CD4 (p = 0.007), CD8 (p = 0.006), and FOXP3 (p = 0.001). However, the intratumoral CD8 to FOXP3 ratio showed a trend to be lower in BRCA2-mutated tumors suggesting a more suppressed tumor immune microenvironment. Our findings provide a rationale for the future use of immune oncological approaches in BRCA2-mutated prostate cancer and may encourage efforts to target immunosuppressive T-cell populations to prime tumors for immunotherapy.

Exploring molecular profiles of uterine carcinosarcoma with alterations in the chromatin remodeling pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5587-5587
Author(s):  
Annelise M. Wilhite ◽  
Sharon Wu ◽  
Joanne Xiu ◽  
Rodney Paul Rocconi ◽  
Britt Kristina Erickson ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Immune Cell ◽  
Excision Repair ◽  
Statistical Significance ◽  
Uterine Carcinosarcoma ◽  
Chi Square ◽  
Whole Transcriptome Sequencing ◽  
Insurance Claims Data ◽  
Molecular Profiles ◽  
The Impact

5587 Background: In a preliminary data analysis to identify prognostic molecular biomarkers in uterine carcinosarcoma (UCS), we found that alterations in KMT2C, a gene involved in the chromatin remodeling pathway, correlated with improved survival. We sought to explore relevant biomarkers of KMT2C-mutated (KMT2C-mut) tumors compared to wildtype (KMT2C-wt) tumors. Methods: Tumor samples were analyzed using next generation sequencing (NGS) of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). Microsatelite instability (MSI) was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be <0.05. Results: Molecular analysis was performed on 1,144 UCS tumors. 7.7% were found to be KMT2C-mut. Patients with pathogenic alterations in KMT2C had longer median OS than patients without (OS not yet reached vs 19.0 months HR(95% CI): 0.37(0.19-0.72) p< 0.01). The most common mutations in KMT2C-mut tumors are shown in Table and resulted in more frequent dysregulation in the following pathways compared to KMT2C-wt tumors: chromatin remodeling (100% vs 28%; q<0.01), WNT (39% vs 12%; q=0.01), base/nucleotide excision repair (29% vs 5%; q<0.01), homologous recombination (26% vs 6%; q=0.02), DNA damage sensors (23% vs 4%; q=0.02) and Fanconi anemia (13% vs 1%; q=0.04). KMT2C-mut tumors were more frequently MSI-H (32% vs 6%; q<0.01) and TMB-H (42% vs 5%; q<0.01). Among MSS tumors, KMT2C-mut tumors had increased mutations in JAK1 and POLE (q<0.01) and higher frequency of TMB-H (24% vs 1%; q<0.01) than KMT2C-wt tumors. Additionally, MSS patients with KMT2C-mut had longer OS than patients with KMT2C-wt tumors (OS not yet reached vs 18.9 months; HR(95% CI): 0.33(0.15-0.75) p< 0.01). Conclusions: Mutations in KMT2C correlate with improved OS in UCS. KMT2C-mut tumors have distinct molecular profiles from wild type tumors. They exhibit greater immunogenicity, including more frequent MSI-H and TMB-H. This suggests a potential role for Immune-oncology (IO) therapy. Further study of the impact of IO therapies in the cohort is warranted as this may contribute to the improved survival of these patients.[Table: see text]

scholarly journals CMET-18. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi55-vi55
Author(s):  
Adam Lauko ◽  
Assad Ali ◽  
Soumya Sagar ◽  
Addison Barnett ◽  
Hong Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Checkpoint Inhibitors ◽  
Care Center ◽  
Tertiary Care ◽  
Wild Type ◽  
Chi Square ◽  
Kras Mutations ◽  
Mutational Status

Abstract BACKGROUND Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

Are the presenting characteristics and prognosis of primary salivary gland-type lung cancers (SG) similar to those of other non-small cell lung cancers (NSCLC)?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7054-7054
Author(s):  
John M. Varlotto ◽  
Suhail M. Ali ◽  
Malcolm M. DeCamp ◽  
John Charles Flickinger ◽  
Abram Recht ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Proportional Hazards ◽  
Stage Iv ◽  
Cox Proportional Hazards ◽  
Stage I ◽  
Optimal Care ◽  
Chi Square ◽  
Cancer Specific Survival ◽  
Lung Cancers ◽  
Survival Difference

7054 Background: SG, both adenoid cystic (ACC) and mucoepidermoid (ME) sub-types, are rare lung cancers. We choose to investigate the incidence of these rare sub-types and assess their difference in presentation and prognostic characteristics in comparison to adenocarcinomas (Ad) and squamous cell carcinomas (SCC) during the same time period. Methods: The SEER-17 database was used to collect data during the years 1988-2008. Differences between populations were determined by the chi-square test. Survival curves were generated as Kaplan-Meier techniques. Cox proportional hazards test was used to compare survival differences. Results: During the 20-year study period, ACC (n =100) and ME (n= 178) accounted for 0.03% and 0.06% of NSCLCs. Mean follow-up was 34.5 months for all patients. In comparison to ACC, patients with ME were significantly more likely to be younger (52 yr vs. 60yr), Asian(11.7% vs. 7%), have Stage I disease (62.9% vs 24.0%), and less likely to be in the mainstem bronchi (17.2% vs. 6.3%). In comparison to patients with patients presenting with either SCC or Ad, both ME and ACC were significantly less likely to present with Stage IV disease (26.6% SCC, 41.29% Ad, 16.73% SG), have nodal involvement (35.1% SCC, 27.4% Ad, 23.37% SG), and be older (70 SCC, 68 Ad, 58 years SG). Stratified by stage and treatment, there was no survival (OS) or disease-specific survival difference (DSS) between ACC and ME. The OS of the combined group of ME and ACC was significantly better stage per stage than either Ad (Hazard ratio (HR) range = 0.26- 041), and SCC (HR range = 0.17-0.56). Lung Cancer-Specific survival at 2,3,5 years for surgically-resected Stage I ACC and ME were 83.5%, 80.4%, and 80.4%; and 82.6%, 78.0% and 78%, respectively. Conclusions: Patients with ACC and ME have rare sub-types of lung cancer that present differently and have better survival than patients presenting with either of the more common histologic sub-types (SCC and Ad) of NSCLC. We encourage prospective, multi-institutional studies of these rare sub-types so that care can be optimized. Optimal care may differ for SG because of their stage per stage better prognosis than other NSCLCs.

scholarly journals MET Exon 14 Mutations in Non–Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression

2016 ◽  
Vol 34 (7) ◽  
pp. 721-730 ◽  
Author(s):  
Mark M. Awad ◽  
Geoffrey R. Oxnard ◽  
David M. Jackman ◽  
Daniel O. Savukoski ◽  
Dimity Hall ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Molecular Subtype ◽  
Stage Iv ◽  
Small Cell ◽  
Chromosome 7 ◽  
Small Cell Lung ◽  
Genomic Amplification ◽  
Lung Cancers ◽  
Never Smokers ◽  
Egfr Mutant

Purpose Non–small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations. Patients and Methods We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available. Results MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14–mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14–mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14–mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14–wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib. Conclusion MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.

Lung cancer-derived EGFR mutations affect responses to tyrosine kinase inhibitors, but not to monoclonal antibodies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3044-3044
Author(s):  
M. Dechant ◽  
M. Peipp ◽  
T. Schneider-Merck ◽  
T. Beyer ◽  
J. J. Lammerts van Bueren ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Immune Cell ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Wild Type ◽  
Western Blots

3044 Background: The epidermal growth factor receptor (EGFR) serves as a molecular target for novel cancer therapeutic approaches. Two groups of anti-EGFR agents are clinically most advanced: tyrosine kinase inhibitors (TKI) and EGFR antibodies. Recently, somatic mutations in the EGFR kinase domain were identified in tumors from lung cancer patients, which affected EGFR signaling and which correlated with responses to TKI therapy. Since interference with tumor cell signaling is also considered an important mechanism of action for therapeutic antibodies, we investigated the influence of these intracellular EGFR mutations on cell killing by EGFR antibodies, in comparison to TKI. Methods: For this purpose, we established an EGF-responsive, non-transformed cell line model for the three most common lung cancer-derived intracellular EGFR mutations L858R, G719S and delE746-A750. EGFR phosphorylation status was analyzed by Western Blots. MTT assays were performed to compare TKI gefitinib and erlotinib with antibodies C225 and 2F8 in their capacity to inhibit cell growth of wild type and mutated EGFR-transfectants. Impact of intracellular EGFR mutations on immune cell-mediated killing by EGFR antibodies was measured in classical 3 hours 51-chromium-release assays. Results: Mutated EGFR transfected cells were growth factor- responsive, and significantly more sensitive to both gefitinib and erlotinib than wild type (WT) EGFR expressing cells. However, anti-tumor effector functions of both EGFR-directed IgG1 antibodies—chimeric C225 and fully human 2F8—were not affected by the mutations. Conclusions: Intracellular mutations of EGFR may, therefore, be less relevant for EGFR antibodies than for TKI. No significant financial relationships to disclose.

scholarly journals Measles Virus Selectively Blind to Signaling Lymphocytic Activation Molecule (SLAM; CD150) Is Attenuated and Induces Strong Adaptive Immune Responses in Rhesus Monkeys

2010 ◽  
Vol 84 (7) ◽  
pp. 3413-3420 ◽  
Author(s):  
Vincent H. J. Leonard ◽  
Gregory Hodge ◽  
Jorge Reyes-del Valle ◽  
Michael B. McChesney ◽  
Roberto Cattaneo
Keyword(s):  
Rhesus Monkeys ◽  
Measles Virus ◽  
Immune Cell ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Neutralizing Antibody ◽  
Cell Receptor ◽  
Control Group ◽  
Wild Type ◽  
Signaling Lymphocytic Activation Molecule

ABSTRACT The signaling lymphocytic activation molecule (SLAM; CD150) is the immune cell receptor for measles virus (MV). To assess the importance of the SLAM-MV interactions for virus spread and pathogenesis, we generated a wild-type IC-B MV selectively unable to recognize human SLAM (SLAM-blind). This virus differs from the fully virulent wild-type IC-B strain by a single arginine-to-alanine substitution at amino acid 533 of the attachment protein hemagglutinin and infects cells through SLAM about 40 times less efficiently than the isogenic wild-type strain. Ex vivo, this virus infects primary lymphocytes at low levels regardless of SLAM expression. When a group of six rhesus monkeys (Macaca mulatta) was inoculated intranasally with the SLAM-blind virus, no clinical symptoms were documented. Only one monkey had low-level viremia early after infection, whereas all the hosts in the control group had high viremia levels. Despite minimal, if any, viremia, all six hosts generated neutralizing antibody titers close to those of the control monkeys while MV-directed cellular immunity reached levels at least as high as in wild-type-infected monkeys. These findings prove formally that efficient SLAM recognition is necessary for MV virulence and pathogenesis. They also suggest that the selectively SLAM-blind wild-type MV can be developed into a vaccine vector.

scholarly journals Acquired Substrate Preference for GAB1 Protein Bestows Transforming Activity to ERBB2 Kinase Lung Cancer Mutants

2013 ◽  
Vol 288 (23) ◽  
pp. 16895-16904 ◽  
Author(s):  
Ying-Xin Fan ◽  
Lily Wong ◽  
Michael P. Marino ◽  
Wu Ou ◽  
Yi Shen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Transformation ◽  
Kinase Domain ◽  
Tumor Formation ◽  
Dominant Negative ◽  
Substrate Preference ◽  
Wild Type ◽  
Lung Cancers ◽  
Binding Cleft

Activating mutations in the αC-β4 loop of the ERBB2 kinase domain, such as ERBB2YVMA and ERBB2G776VC, have been identified in human lung cancers and found to drive tumor formation. Here we observe that the docking protein GAB1 is hyper-phosphorylated in carcinomas from transgenic mice and in cell lines expressing these ERBB2 cancer mutants. Using dominant negative GAB1 mutants lacking canonical tyrosine residues for SHP2 and PI3K interactions or lentiviral shRNA that targets GAB1, we demonstrate that GAB1 phosphorylation is required for ERBB2 mutant-induced cell signaling, cell transformation, and tumorigenesis. An enzyme kinetic analysis comparing ERBB2YVMA to wild type using physiologically relevant peptide substrates reveals that ERBB2YVMA kinase adopts a striking preference for GAB1 phosphorylation sites as evidenced by ∼150-fold increases in the specificity constants (kcat/Km) for several GAB1 peptides, and this change in substrate selectivity was predominantly attributed to the peptide binding affinities as reflected by the apparent Km values. Furthermore, we demonstrate that ERBB2YVMA phosphorylates GAB1 protein ∼70-fold faster than wild type ERBB2 in vitro. Notably, the mutation does not significantly alter the Km for ATP or sensitivity to lapatinib, suggesting that, unlike EGFR lung cancer mutants, the ATP binding cleft of the kinase is not significantly changed. Taken together, our results indicate that the acquired substrate preference for GAB1 is critical for the ERBB2 mutant-induced oncogenesis.

Host transcriptomic signatures associated with dysbiosis in a preclinical model of lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3107-3107
Author(s):  
Mariam El-Ashmawy ◽  
Benjamin Wu ◽  
Jun-Chieh Tsay ◽  
Brendan Franca ◽  
Luisanny Perez ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Flow Cytometry ◽  
Immune Cell ◽  
Sequence Data ◽  
Gene Expression Signature ◽  
Th2 Cells ◽  
Lower Airway ◽  
Preclinical Model ◽  
Wild Type ◽  
Experimental Conditions

3107 Background: Enrichment of the lower airway microbiota with oral commensals has been associated with transcriptomic changes affecting several inflammatory pathways associated with non-small cell lung cancer (NSCLC) development and progression. Using a mouse model of NSCLC, we evaluated the effects of lower airway dysbiosis on tumor progression and host transcriptomics. Methods: Preclinical model of lung cancer was constructed by introducing luminescence-tagged Kras mutated cells into C57/B6 mice, causing lung cancer to develop. Lower airway dysbiosis was induced by weekly intratracheal challenge with either PBS or Veillonella parvula in wild type and lung cancer mice. Experiments were repeated twice to evaluate for survival as well as lower airway host response using flow cytometry and RNA sequencing (HiSeq). Sequence data was processed using a validated mouse gene expression signature matrix with cibersort from https://cibersort.stanford.edu and DESeq using FDR correction. Results: In wild type mice, lower airway dysbiosis with Veillonella did not affect the survival, weight gain or airway lumen diameter. Among lung cancer mice, dysbiosis led to increased mortality, weight loss, and tumor burden. Multiple transcriptomic signatures were identified among the dysbiosis groups (both in WT and lung cancer mice). Unsupervised hierarchical clustering of immune cell profiles using cibersort on whole transcriptome showed near perfect separation between the four experimental conditions. Amongst the most differentially enriched immune cell subsets, we identified that lung dysbiosis upregulates genes annotated to Th1 and Th2 cells (p < 0.01, q < 0.2). Using flow cytometry, we identified that PD-1, IL-17, and ROR-gamma are differentially expressed in CD4+ cells in dysbiosis conditions, and these patterns are consistent in whole RNA transcriptome. Conclusions: Transcriptomic signatures reveal immune profiles associated with dysbiosis, an experimental condition associated with worse outcomes in lung cancer. This investigation provides novel insights into how disruption of the lower airway microbiome may contribute to the pathogenesis of NSCLC.

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