Prediction of cancer treatment response from histopathology images through imputed transcriptomics.

Advances in artificial intelligence have paved the way for leveraging hematoxylin and eosin (H&E)-stained tumor slides for precision oncology. We present ENLIGHT-DeepPT, an approach for predicting response to multiple targeted and immunotherapies from H&E-slides. In difference from existing approaches that aim to predict treatment response directly from the slides, ENLIGHT-DeepPT is an indirect two-step approach consisting of (1) DeepPT, a new deep-learning framework that predicts genome-wide tumor mRNA expression from slides, and (2) ENLIGHT, which predicts response based on the DeepPT inferred expression values. DeepPT successfully predicts transcriptomics in all 16 TCGA cohorts tested and generalizes well to two independent datasets. Our key contribution is showing that ENLIGHT-DeepPT successfully predicts true responders in five independent patients' cohorts involving four different treatments spanning six cancer types with an overall odds ratio of 2.44, increasing the baseline response rate by 43.47% among predicted responders, without the need for any treatment data for training. Furthermore, its prediction accuracy on these datasets is comparable to a supervised approach predicting the response directly from the images, which needs to be trained and tested on the same cohort. ENLIGHT-DeepPT future application could provide clinicians with rapid treatment recommendations to an array of different therapies and importantly, may contribute to advancing precision oncology in developing countries.

SOX9 drives KRAS-induced lung adenocarcinoma progression and suppresses anti-tumor immunity.

The SOX9 transcription factor ensures proper tissue development and homeostasis and has been implicated in promoting tumor progression. However, the role of SOX9 as a driver of lung adenocarcinoma (LUAD), or any cancer, remains unclear. Using CRISPR/Cas9 and Cre-LoxP gene knockout approaches in the KrasG12D-driven mouse LUAD model, we found that loss of Sox9 significantly reduces lung tumor development, burden and progression, contributing to significantly longer overall survival. SOX9 consistently drove organoid growth in vitro, but SOX9-promoted tumor growth was significantly attenuated in immunocompromised mice compared to syngeneic mice. We demonstrate that SOX9 suppresses immune cell infiltration and functionally suppresses tumor associated CD8+ T, natural killer and dendritic cells. These data were validated by flow cytometry, gene expression, RT-qPCR, and immunohistochemistry analyses in KrasG12D-driven murine LUAD, then confirmed by interrogating bulk and single-cell gene expression repertoires and immunohistochemistry in human LUAD. Notably, SOX9 significantly elevates collagen-related gene expression and substantially increases collagen fibers. We propose that SOX9 increases tumor stiffness and inhibits tumor-infiltrating dendritic cells, thereby suppressing CD8+ T cell and NK cell infiltration and activity. Thus, SOX9 drives KrasG12D-driven lung tumor progression and inhibits anti-tumor immunity at least partly by modulating the tumor microenvironment.

Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.

LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung cancer cells, but not in KrasG12D/+;p53-/- (KP) lung cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by ferroptosis inhibitor. Taken together, we demonstrate that autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting ferroptosis. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.

Racial disparities in follow-up care of early-stage lung cancer survivors.

PURPOSE: To investigate if race impacts receipt of follow-up care in lung cancer survivors, we conducted a cross-sectional study in lung cancer survivors recruited through the New Jersey State Cancer Registry (NJSCR). METHODS: Between May 2019 and December 2019, survivors of early-stage NSCLC were identified and recruited from the NJSCR. Eligible participants were asked to complete a paper survey questionnaire and medical record release form sent to them by mail. RESULTS: Of the 112 survivors included in the analysis, 78 (70%) were non-Hispanic (NH) Whites and 34 (30%) were NH Blacks. Mean age was 67 years, 61% were female, and 92% had cancer in remission. A total of 82% of participants reported receiving a surveillance scan (CT or PET) within 1 year of completing the study survey. More NH White survivors received a scan within a year compared to NH Black survivors (89% vs 70%; p = 0.02). More NH White survivors (94%) reported that they were informed of the need for follow-up care by their provider compared to NH Blacks (71%; p = 0.002). Only 57% survivors reported receiving a treatment summary. Significant barriers to care were out-of-pocket costs (24%), non-coverage of test (12.5%), and lack of insurance (10%). CONCLUSIONS: Significant disparity was identified between NH Blacks and NH Whites in receipt of surveillance scans, as well as in receiving information about need for follow-up care. Low income, lack of insurance, and other financial concerns were identified as significant barriers to follow-up care. IMPLICATIONS FOR CANCER SURVIVORS: Future interventions to increase survivorship care should target specific unmet needs identified in each survivor population.

Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors.

Immunometabolic reprogramming due to adenosine produced by CD73 (encoded by the 5'-ectonucleotidase gene NT5E) is a recognized immunosuppressive mechanism contributing to immune evasion in solid tumors. Adenosine is not only known to contribute to tumor progression, but it has specific roles in driving dysfunction of immune cells, including natural killer (NK) cells. Here, we engineered human NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73. In doing so, the engineered NK cells not only impaired adenosinergic metabolism driven by the hypoxic uptake of ATP by cancer cells in a model of non-small-cell lung cancer, but also mediated killing of tumor cells due to the specific recognition of overexpressed CD73. This resulted in a 'single agent' immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73+ tumors and enhancing intratumoral activation.

Inhibition of Mtorc1/2 and DNA-PK via CC-115 Synergizes with Carboplatin and Paclitaxel in Lung Squamous Cell Carcinoma.

Only a small percentage (<1%) of patients with late-stage lung squamous cell carcinoma (LUSC) are eligible for targeted therapy. Because PI3K/AKT/mTOR signaling, particularly Phosphatidylinositol 3-kinase CA (PIK3CA), is dysregulated in two-thirds of LUSC, and DNA damage response pathways are enriched in LUSC, we tested whether CC-115, a dual mTORC1/2 and DNA-PK inhibitor, sensitizes LUSC to chemotherapy. We demonstrate that CC-115 synergizes with carboplatin in six of 14 NSCLC cell lines, primarily PIK3CA-mutant LUSC. Synergy was more common in cell lines that had decreased basal levels of activated AKT and DNA-PK, evidenced by reduced P-S473-AKT, P-Th308-AKT, and P-S2056-DNA-PKcs. CC-115 sensitized LUSC to carboplatin by inhibiting chemotherapy-induced AKT activation and maintaining apoptosis, particularly in PIK3CA-mutant cells lacking wild-type (WT) TP53. In addition, pathway analysis revealed that enrichments in the IFNα and IFNγ pathways were significantly associated with synergy. In multiple LUSC patient-derived xenograft and cell line tumor models, CC-115 plus platinum-based doublet chemotherapy significantly inhibited tumor growth and increased overall survival as compared with either treatment alone at clinically relevant dosing schedules. IHC and immunoblot analysis of CC-115-treated tumors demonstrated decreased P-Th308-AKT, P-S473-AKT, P-S235/236-S6, and P-S2056-DNA-PKcs, showing direct pharmacodynamic evidence of inhibited PI3K/AKT/mTOR signaling cascades. Because PI3K pathway and DNA-PK inhibitors have shown toxicity in clinical trials, we assessed toxicity by examining weight and numerous organs in PRKDC-WT mice, which demonstrated that the combination treatment does not exacerbate the clinically accepted side effects of standard-of-care chemotherapy. This preclinical study provides strong support for the further investigation of CC-115 plus chemotherapy in LUSC.

Smoking-associated Downregulation of FILIP1L Enhances Lung Adenocarcinoma Progression Through Mucin Production, Inflammation, and Fibrosis.

Lung adenocarcinoma (LUAD) is the major subtype in lung cancer, and cigarette smoking is essentially linked to its pathogenesis. We show that downregulation of Filamin A interacting protein 1-like (FILIP1L) is a driver of LUAD progression. Cigarette smoking causes its downregulation by promoter methylation in LUAD. Loss of FILIP1L increases xenograft growth, and, in lung-specific knockout mice, induces lung adenoma formation and mucin secretion. In syngeneic allograft tumors, reduction of FILIP1L and subsequent increase in its binding partner, prefoldin 1 (PFDN1) increases mucin secretion, proliferation, inflammation, and fibrosis. Importantly, from the RNA-sequencing analysis of these tumors, reduction of FILIP1L is associated with upregulated Wnt/ß-catenin signaling, which has been implicated in proliferation of cancer cells as well as inflammation and fibrosis within the tumor microenvironment. Overall, these findings suggest that down-regulation of FILIP1L is clinically relevant in LUAD, and warrant further efforts to evaluate pharmacologic regimens that either directly or indirectly restore FILIP1L-mediated gene regulation for the treatment of these neoplasms. Significance: This study identifies FILIP1L as a tumor suppressor in LUADs and demonstrates that downregulation of FILIP1L is a clinically relevant event in the pathogenesis and clinical course of these neoplasms.

JAK/STAT of all trades: linking inflammation with cancer development, tumor progression and therapy resistance.

Inflammation is at the forefront of carcinogenesis, tumor progression and resistance to therapy. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling axis is a central pathway that mediates the cellular response to inflammation and contributes to carcinogenesis. The JAK/STAT pathway coordinates intercellular communication between tumor cells and their immune microenvironment, and JAK/STAT activation leads to the expression of a variety of proteins involved in cell proliferation, cell survival, stemness, self-renewal, evasion of immunosurveillance mechanisms and overall tumor progression. Activation of JAK/STAT signaling also mediates resistance to radiation therapy or cytotoxic agents and modulates tumor cell responses to molecularly targeted and immune modulating drugs. Despite extensive research focused on understanding its signaling mechanisms and downstream phenotypic and functional consequences in hematological disorders, the importance of JAK/STAT signaling in solid tumor initiation and progression has been underappreciated. We highlight the role of chronic inflammation in cancer, the epidemiological evidence for contribution of JAK/STAT to carcinogenesis, the current cancer prevention measures involving JAK/STAT inhibition and the impact of JAK/STAT signaling activity on cancer development, progression and treatment resistance. We also discuss recent therapeutic advances in targeting key factors within the JAK/STAT pathway with single agents and the use of these agents in combination with other targeted therapies and immune checkpoint inhibitors.

FILIP1L Loss Is a Driver of Aggressive Mucinous Colorectal Adenocarcinoma and Mediates Cytokinesis Defects through PFDN1.

Aneuploid mucinous colorectal adenocarcinoma (MAC) is an aggressive subtype of colorectal cancer with poor prognosis. The tumorigenic mechanisms in aneuploid MAC are currently unknown. Here we show that downregulation of Filamin A-interacting protein 1-like (FILIP1L) is a driver of MAC. Loss of FILIP1L increased xenograft growth, and, in colon-specific knockout mice, induced colonic epithelial hyperplasia and mucin secretion. The molecular chaperone prefoldin 1 (PFDN1) was identified as a novel binding partner of FILIP1L at the centrosomes throughout mitosis. FILIP1L was required for proper centrosomal localization of PFDN1 and regulated proteasome-dependent degradation of PFDN1. Importantly, increased PFDN1, caused by downregulation of FILIP1L, drove multinucleation and cytokinesis defects in vitro and in vivo, which were confirmed by time-lapse imaging and 3D cultures of normal epithelial cells. Overall, these findings suggest that downregulation of FILIP1L and subsequent upregulation of PFDN1 is a driver of the unique neoplastic characteristics in aggressive aneuploid MAC. SIGNIFICANCE: This study identifies FILIP1L as a tumor suppressor in mucinous colon cancer and demonstrates that FILIP1L loss results in aberrant stabilization of a centrosome-associated chaperone protein to drive aneuploidy and disease progression.

Whole-Exome Profiling of NSCLC Among African Americans.

INTRODUCTION: Lung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States, especially among men. Although significant progress has been made profiling the genomic makeup of lung cancer in EAs, AAs continue to be underrepresented. Our objective was to chart the genome-wide landscape of somatic mutations in lung cancer tumors from AAs. METHODS: In this study, we used the whole-exome sequencing of 82 tumor and noninvolved tissue pairs from AAs. Patients were selected from an ongoing case-control study conducted by the National Cancer Institute and the University of Maryland. RESULTS: Among all samples, we identified 178 significantly mutated genes (p < 0.05), five of which passed the threshold for false discovery rate (p < 0.1). In lung adenocarcinoma (LUAD) tumors, mutation rates in STK11 (p = 0.05) and RB1 (p = 0.008) were significantly higher in AA LUAD tumors (25% and 13%, respectively) compared with The Cancer Genome Atlas EA samples (14% and 4%, respectively). In squamous cell carcinomas, mutation rates in STK11 (p = 0.002) were significantly higher among AA (8%) than EA tumors from The Cancer Genome Atlas (1%). Integrated somatic mutation data with CIBERSORT (Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts) data analysis revealed LUAD tumors from AAs carrying STK11 mutations have decreased interferon signaling. CONCLUSIONS: Although a considerable degree of the somatic mutation landscape is shared between EAs and AAs, discrete differences in mutation frequency in potentially important oncogenes and tumor suppressors exist. A better understanding of the molecular basis of lung cancer in AA patients and leveraging this information to guide clinical interventions may help reduce disparities.

G protein-coupled kisspeptin receptor induces metabolic reprograming and tumorigenesis in estrogen receptor-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly metastatic and deadly disease. TNBC tumors lack estrogen receptor (ERα), progesterone receptor (PR), and HER2 (ErbB2) and exhibit increased glutamine metabolism, a requirement for tumor growth. The G protein-coupled kisspeptin receptor (KISS1R) is highly expressed in patient TNBC tumors and promotes malignant transformation of breast epithelial cells. This study found that TNBC patients displayed elevated plasma kisspeptin levels compared with healthy subjects. It also provides the first evidence that in addition to promoting tumor growth and metastasis in vivo, KISS1R-induced glutamine dependence of tumors. In addition, tracer-based metabolomics analyses revealed that KISS1R promoted glutaminolysis and nucleotide biosynthesis by increasing c-Myc and glutaminase levels, key regulators of glutamine metabolism. Overall, this study establishes KISS1R as a novel regulator of TNBC metabolism and metastasis, suggesting that targeting KISS1R could have therapeutic potential in the treatment of TNBC.

Author Correction: Recurrent PTPRT/JAK2 mutations in lung adenocarcinoma among African Americans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Recurrent PTPRT/JAK2 mutations in lung adenocarcinoma among African Americans.

Reducing or eliminating persistent disparities in lung cancer incidence and survival has been challenging because our current understanding of lung cancer biology is derived primarily from populations of European descent. Here we show results from a targeted sequencing panel using NCI-MD Case Control Study patient samples and reveal a significantly higher prevalence of PTPRT and JAK2 mutations in lung adenocarcinomas among African Americans compared with European Americans. This increase in mutation frequency was validated with independent WES data from the NCI-MD Case Control Study and TCGA. We find that patients carrying these mutations have a concomitant increase in IL-6/STAT3 signaling and miR-21 expression. Together, these findings suggest the identification of these potentially actionable mutations could have clinical significance for targeted therapy and the enrollment of minority populations in clinical trials.

Strategy to enhance lung cancer treatment by five essential elements: inhalation delivery, nanotechnology, tumor-receptor targeting, chemo- and gene therapy.

Non-Small Cell Lung Carcinoma (NSCLC), is the most common type of lung cancer (more than 80% of all cases). Small molecule Tyrosine Kinase (TK) Inhibitors acting on the Epidermal Growth Factor Receptors (EGFRs) are standard therapies for patients with NSCLC harboring EGFR-TK inhibitor-sensitizing mutations. However, fewer than 10 % of patients with NSCLC benefit from this therapy. Moreover, even the latest generation of EGFR inhibitors can cause severe systemic toxicities and are ineffective in preventing non-canonical EGFR signaling. In order to minimize and even overcome these limitations, we are proposing a novel multi-tier biotechnology treatment approach that includes: (1) suppression of all four types of EGFR-TKs by a pool of small interfering RNAs (siRNAs); (2) induction of cell death by an anticancer drug, (3) enhancing the efficiency of the treatment by the local inhalation delivery of therapeutic agents directly to the lungs (passive targeting), (4) active receptor-mediated targeting of the therapy specifically to cancer cells that in turn should minimize adverse side effects of treatment and (5) increasing the stability, solubility, and cellular penetration of siRNA and drug by using tumor targeted Nanostructured Lipid Carriers (NLC). Methods: NLCs targeted to NSCLC cells by a synthetic Luteinizing Hormone-Releasing Hormone (LHRH) decapeptide was used for the simultaneous delivery of paclitaxel (TAX) and a pool of siRNAs targeted to the four major forms of EGFR-TKs. LHRH-NLC-siRNAs-TAX nanoparticles were synthesized, characterized and tested in vitro using human lung cancer cells with different sensitivities to gefitinib (inhibitor of EGFR) and in vivo on an orthotopic NSCLC mouse model. Results: Proposed nanoparticle-based complex containing an anticancer drug, inhibitors of different types of EGFR-TKs and peptide targeted to the tumor-specific receptors (LHRH-NLC-siRNAs-TAX) demonstrated a favorable organ distribution and superior anticancer effect when compared with treatment by a single drug, inhibitor of one EGFR-TK and non-targeted therapy. Conclusions: The use of a multifunctional NLC-based delivery system substantially enhanced the efficiency of therapy for NSCLC and possibly will limit adverse side effects of the treatments. The results obtained have the potential to significantly impact the field of drug delivery and to improve the efficiency of therapy of lung and other types of cancer.

pathCHEMO, a generalizable computational framework uncovers molecular pathways of chemoresistance in lung adenocarcinoma.

Despite recent advances in discovering a wide array of novel chemotherapy agents, identification of patients with poor and favorable chemotherapy response prior to treatment administration remains a major challenge in clinical oncology. To tackle this challenge, we present a generalizable genome-wide computational framework pathCHEMO that uncovers interplay between transcriptomic and epigenomic mechanisms altered in biological pathways that govern chemotherapy response in cancer patients. Our approach is tested on patients with lung adenocarcinoma who received adjuvant standard-of-care doublet chemotherapy (i.e., carboplatin-paclitaxel), identifying seven molecular pathway markers of primary treatment response and demonstrating their ability to predict patients at risk of carboplatin-paclitaxel resistance in an independent patient cohort (log-rank p-value = 0.008, HR = 10). Furthermore, we extend our method to additional chemotherapy-regimens and cancer types to demonstrate its accuracy and generalizability. We propose that our model can be utilized to prioritize patients for specific chemotherapy-regimens as a part of treatment planning.

Relationship between West African ancestry with lung cancer risk and survival in African Americans.

PURPOSE: African Americans, especially men, have a higher incidence of lung cancer compared with all other racial and ethnic groups in the US. Self-reported race is frequently used in genomic research studies to capture an individual's race or ethnicity. However, it is clear from studies of genetic admixture that human genetic variation does not segregate into the same biologically discrete categories as socially defined categories of race. Previous studies have suggested that the degree of West African ancestry among African Americans can contribute to cancer risk in this population, though few studies have addressed this question in lung cancer. METHODS: Using a genetic ancestry panel of 100 SNPs, we estimated West African, European, and Native American ancestry in 1,407 self-described African Americans and 2,413 European Americans. RESULTS: We found that increasing West African ancestry was associated with increased risk of lung cancer among African American men (ORQ5 vs Q1 = 2.55 (1.45-4.48), p = 0.001), while no association was observed in African American women (ORQ5 vs Q1 = 0.90 (0.51-1.59), p = 0.56). This relationship diminished following adjustment for income and education. CONCLUSIONS: Genetic ancestry is not a major contributor to lung cancer risk or survival disparities.

A Novel Acquired Exon 20 EGFR M766Q Mutation in Lung Adenocarcinoma Mediates Osimertinib Resistance but is Sensitive to Neratinib and Poziotinib.

INTRODUCTION: Osimertinib is an effective third-generation tyrosine kinase inhibitor (TKI) for EGFR-mutant lung cancers. However, treatment for patients with acquired resistance to osimertinib remains challenging. We characterized a novel EGFR mutation in exon 20 that was acquired while on osimertinib. METHODS: A 79-year-old woman had disease progression during third-line treatment with osimertinib for an EGFR L858R/T790M-mutant lung cancer. Sequencing of circulating cell-free DNA showed EGFR L858R, an acquired novel EGFR M766Q mutation in exon 20, and no evidence of EGFR T790M. Homology modeling was performed to investigate the effects of M766Q on binding to osimertinib. L858R and L858R/M766Q mutations were retrovirally introduced into Ba/F3 and NIH/3T3 cells and evaluated for sensitivity to first-generation (erlotinib), second-generation (afatinib, neratinib, and poziotinib), and third-generation TKIs (osimertinib) by cell viability and colony-formation assays. EGFR-mediated signaling pathways were interrogated by western blotting. RESULTS: Modeling suggested that EGFR M766Q could disrupt osimertinib binding. L858R/M766Q double-mutant cells were 12-fold more resistant to osimertinib, and more than 250-fold more resistant to erlotinib and afatinib, as compared to L858R-mutant cells. In contrast, double-mutant cells remained sensitive to neratinib and poziotinib at clinically relevant doses (concentration that inhibits 50%, 4.3 and 1.3 nM, respectively). This was corroborated by the effects of the TKIs on colony formation and EGFR signaling. CONCLUSIONS: Acquisition of EGFR M766Q exon 20 mutation is a novel mechanism of acquired resistance to osimertinib. EGFR-mutant lung cancers with an acquired EGFR M766Q mutation in the setting of osimertinib resistance may be sensitive to neratinib and poziotinib.

Circulating Inflammation Proteins Associated With Lung Cancer in African Americans.

INTRODUCTION: Lung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States. We and others have previously shown a relationship between immune and inflammation proteins with lung cancer in EAs. Our aim was to investigate the etiologic relationship between inflammation and lung cancer in AAs. METHODS: We adopted a two-stage, independent study design (discovery cases, n = 316; control cases, n = 509) (validation cases, n = 399; control cases, n = 400 controls) and measured 30 inflammation proteins in blood using Meso Scale Discovery V- PLEX multiplex assays. RESULTS: We identified and validated 10 proteins associated with lung cancer in AAS, some that were common between EAs and AAs (C-reactive proteins [OR: 2.90; 95% confidence interval (CI): 1.99-4.22], interferon γ [OR: 1.55; 95% CI: 1.10-2.19], interleukin 6 [OR: 6.28; 95% CI: 4.10-9.63], interleukin 8 [OR: 2.76; 95% CI: 1.92-3.98]) and some that are only observed among AAs (interleukin 10 [OR: 1.69; 95% CI: 1.20-2.38], interleukin 15 [OR: 2.83; 95% CI: 1.96-4.07], interferon gamma-induced protein 10 [OR: 1.54; 95% CI: 1.09-2.18], monocyte chemotactic protein-4 [OR: 0.54; 95% CI: 0.38-0.76], macrophage inflammatory protein-1 alpha [OR: 1.57; 95% CI: 1.12-2.21], and tumor necrosis factor ß [OR: 0.52; 95% CI: 0.37-0.74]). We did not find evidence that either menthol cigarette smoking or global genetic ancestry drove these population differences. CONCLUSIONS: Our results highlight a distinct inflammation profile associated with lung cancer in AAs compared with EAs. These data provide new insight into the etiology of lung cancer in AAs. Further work is needed to understand what drives this relationship with lung cancer and whether these proteins have utility in the setting of early diagnosis.