Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Lung Cancer | Research

Assessing the causal relationship between 731 immunophenotypes and the risk of lung cancer: a bidirectional mendelian randomization study

Authors: Ming Xu, Chengkai Li, Liyan Xiang, Siyue Chen, Lin Chen, Gongxia Ling, Yanqing Hu, Lan Yang, Xiang Yuan, Xiaodong Xia, Hailin Zhang

Published in: BMC Cancer | Issue 1/2024

Login to get access

Abstract

Background

Previous studies have observed a link between immunophenotypes and lung cancer, both of which are closely associated with genetic factors. However, the causal relationship between them remains unclear.

Methods

Bidirectional Mendelian randomization (MR) was performed on publicly available genome-wide association study (GWAS) summary statistics to analyze the causal relationships between 731 immunophenotypes and lung cancer. Sensitivity analyses were conducted to verify the robustness, heterogeneity, and potential horizontal pleiotropy of our findings.

Results

Following Bonferroni adjustment, CD14− CD16+ monocyte (OR = 0.930, 95%CI 0.900–0.960, P = 8.648 × 10− 6, PBonferroni = 0.006) and CD27 on CD24+ CD27+ B cells (OR = 1.036, 95%CI 1.020–1.053, P = 1.595 × 10 − 5, PBonferroni = 0.012) were identified as having a causal role in lung cancer via the inverse variance weighted (IVW) method. At a more relaxed threshold, CD27 on IgD+ CD24+ B cell (OR = 1.035, 95%CI 1.017–1.053, P = 8.666 × 10− 5, PBonferroni = 0.063) and CD27 on switched memory B cell (OR = 1.037, 95%CI 1.018–1.056, P = 1.154 × 10− 4, PBonferroni = 0.084) were further identified. No statistically significant effects of lung cancer on immunophenotypes were found.

Conclusions

The elevated level of CD14− CD16+ monocytes was a protective factor against lung cancer. Conversely, CD27 on CD24+ CD27+ B cell was a risk factor. CD27 on class-switched memory B cells and IgD+ CD24+ B cells were potential risk factors for lung cancer. This research enhanced our comprehension of the interplay between immune responses and lung cancer risk. Additionally, these findings offer valuable perspectives for the development of immunologically oriented therapeutic strategies.
Appendix
Available only for authorised users
Literature
1.
Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet (London England). 2021;398(10299):535–54.PubMedCrossRef
2.
GBD 2019 Lip O and Pharyngeal Cancer Collaborators. The Global, Regional, and National Burden of Adult Lip, oral, and pharyngeal Cancer in 204 countries and territories: a systematic analysis for the global burden of Disease Study 2019. JAMA Oncol. 2023;9(10):1401–16.CrossRef
3.
Alzate JD, Mullen R, Mashiach E, Bernstein K, De Nigris Vasconcellos F, Rotmann L, et al. EGFR-mutated non-small lung cancer brain metastases and radiosurgery outcomes with a focus on leptomeningeal disease. J Neurooncol. 2023;164(2):387–96.PubMedCrossRef
4.
Li C, Lei S, Ding L, Xu Y, Wu X, Wang H, et al. Global burden and trends of lung cancer incidence and mortality. Chin Med J (Engl). 2023;136(13):1583–90.PubMedCrossRef
5.
Freedman ND, Leitzmann MF, Hollenbeck AR, Schatzkin A, Abnet CC. Cigarette smoking and subsequent risk of lung cancer in men and women: analysis of a prospective cohort study. Lancet Oncol. 2008;9(7):649–56.PubMedPubMedCentralCrossRef
6.
GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the global burden of Disease Study 2017. Lancet (London England). 2018;392(10159):1736–88.CrossRef
7.
Wang N, Mengersen K, Tong S, Kimlin M, Zhou M, Hu W. Global, regional, and national burden of lung cancer and its attributable risk factors, 1990 to 2017. Cancer. 2020;126(18):4220–34.PubMedCrossRef
8.
Ji X, Mukherjee S, Landi MT, Bosse Y, Joubert P, Zhu D, et al. Protein-altering germline mutations implicate novel genes related to lung cancer development. Nat Commun. 2020;11(1):2220.ADSPubMedPubMedCentralCrossRef
9.
Gabriel AAG, Atkins JR, Penha RCC, Smith-Byrne K, Gaborieau V, Voegele C, et al. Genetic analysis of Lung Cancer and the germline impact on somatic mutation Burden. JNCI J Natl Cancer Inst. 2022;114(8):1159–66.PubMedCrossRef
10.
Xing S, Hu K, Wang Y. Tumor Immune Microenvironment and Immunotherapy in Non-small Cell Lung Cancer: Update and New challenges. Aging Disease. 2022;13(6):1615–32.PubMedPubMedCentralCrossRef
11.
Cascone T, Fradette J, Pradhan M, Gibbons DL. Tumor Immunology and Immunotherapy of Non-small-cell Lung Cancer. Cold Spring Harbor Perspect Med. 2022;12(5):a037895.CrossRef
12.
Noonepalle Skumar, Karabon R, Chiappinelli L, Villagra KB. Editorial: genetic and epigenetic control of Immune responses. Front Immunol. 2021;12:775101.PubMedPubMedCentralCrossRef
13.
14.
15.
Perfilyeva YV, Abdolla N, Ostapchuk YO, Tleulieva R, Krasnoshtanov VC, Perfilyeva AV, et al. Chronic inflammation contributes to Tumor Growth: possible role of L-Selectin-expressing myeloid-derived suppressor cells (MDSCs). Inflammation. 2019;42(1):276–89.PubMedCrossRef
16.
Karin M, Shalapour S. Regulation of antitumor immunity by inflammation-induced epigenetic alterations. Cell Mol Immunol. 2022;19(1):59–66.PubMedCrossRef
17.
Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018;32(19–20):1267–84.PubMedPubMedCentralCrossRef
18.
Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Therapy. 2021;6:263.CrossRef
19.
Nigam M, Mishra AP, Deb VK, Dimri DB, Tiwari V, Bungau SG, et al. Evaluation of the association of chronic inflammation and cancer: insights and implications. Biomed Pharmacother. 2023;164:115015.PubMedCrossRef
20.
Marcos Rubio A, Everaert C, Van Damme E, De Preter K, Vermaelen K. Circulating immune cell dynamics as outcome predictors for immunotherapy in non-small cell lung cancer. J Immunother Cancer. 2023;11(8):e007023.PubMedPubMedCentralCrossRef
21.
Gaglia G, Burger ML, Ritch CC, Rammos D, Dai Y, Crossland GE, et al. Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma. Cancer Cell. 2023;41(5):871–886e10.PubMedPubMedCentralCrossRef
22.
Sorin M, Karimi E, Rezanejad M, Yu MW, Desharnais L, McDowell SAC, et al. Single-cell spatial landscape of immunotherapy response reveals mechanisms of CXCL13 enhanced antitumor immunity. J Immunother Cancer. 2023;11(2):e005545.PubMedPubMedCentralCrossRef
23.
Maffuid K, Cao Y. Decoding the complexity of Immune-Cancer cell interactions: empowering the future of Cancer Immunotherapy. Cancers. 2023;15(16):4188.PubMedPubMedCentralCrossRef
24.
Wang S, Liu B, Huang J, He H, Li L, Tao A. Cell-in-cell promotes lung cancer malignancy by enhancing glucose metabolism through mitochondria transfer. Exp Cell Res. 2023;429(2):113665.PubMedCrossRef
25.
Rochigneux P, Garcia AJ, Chanez B, Madroszyk A, Olive D, Garon EB. Medical Treatment of Lung Cancer: can Immune cells predict the response? A systematic review. Front Immunol. 2020;11:1036.PubMedPubMedCentralCrossRef
26.
27.
Lim RJ, Liu B, Krysan K, Dubinett SM. Lung Cancer and immunity markers. Cancer epidemiology, biomarkers & Prevention: a publication of the American Association for Cancer Research. Cosponsored Am Soc Prev Oncol. 2020;29(12):2423–30.
28.
Ugel S, Canè S, De Sanctis F, Bronte V. Monocytes in the Tumor Microenvironment. Annu Rev Pathol. 2021;16:93–122.PubMedCrossRef
29.
Kwiecień I, Rutkowska E, Polubiec-Kownacka M, Raniszewska A, Rzepecki P, Domagała-Kulawik J. Blood monocyte subsets with activation markers in relation with macrophages in Non-small Cell Lung Cancer. Cancers. 2020;12(9):2513.PubMedPubMedCentralCrossRef
30.
Orrù V, Steri M, Sidore C, Marongiu M, Serra V, Olla S, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet. 2020;52(10):1036–45.PubMedPubMedCentralCrossRef
31.
Bentham J, Morris DL, Graham DSC, Pinder CL, Tombleson P, Behrens TW, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457–64.PubMedPubMedCentralCrossRef
32.
Zhou W, Liu G, Hung RJ, Haycock PC, Aldrich MC, Andrew AS, et al. Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable mendelian randomization. Int J Cancer. 2021;148(5):1077–86.PubMedCrossRef
33.
Zhou H, Zhang Y, Liu J, Yang Y, Fang W, Hong S, et al. Education and lung cancer: a mendelian randomization study. Int J Epidemiol. 2019;48(3):743–50.PubMedCrossRef
34.
Li Y, Sundquist K, Zhang N, Wang X, Sundquist J, Memon AA. Mitochondrial related genome-wide mendelian randomization identifies putatively causal genes for multiple cancer types. EBioMedicine. 2023;88:104432.PubMedPubMedCentralCrossRef
35.
McKay JD, Hung RJ, Han Y, Zong X, Carreras-Torres R, Christiani DC, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat Genet. 2017;49(7):1126–32.PubMedPubMedCentralCrossRef
36.
Cao RR, Yu XH, Xiong MF, Li XT, Deng FY, Lei SF. The immune factors have complex causal regulation effects on bone mineral density. Front Immunol. 2022;13:959417.PubMedPubMedCentralCrossRef
37.
Gu J, Yan GM, Kong XL, Zhang YY, Huang LH, Lu HM. Assessing the causal relationship between immune traits and systemic lupus erythematosus by bi-directional mendelian randomization analysis. Molecular genetics and genomics: MGG; 2023.CrossRef
38.
Wang C, Zhu D, Zhang D, Zuo X, Yao L, Liu T, et al. Causal role of immune cells in schizophrenia: mendelian randomization (MR) study. BMC Psychiatry. 2023;23(1):590.PubMedPubMedCentralCrossRef
39.
Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2011;40(3):740–52.PubMedCrossRef
40.
Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinf (Oxford England). 2019;35(22):4851–3.
41.
Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife. 2018;7:e34408.PubMedPubMedCentralCrossRef
42.
Sekula P, Del Greco MF, Pattaro C, Köttgen A. Mendelian randomization as an Approach to assess causality using Observational Data. J Am Soc Nephrology: JASN. 2016;27(11):3253–65.PubMedPubMedCentralCrossRef
43.
Sanderson E. Multivariable mendelian randomization and mediation. Cold Spring Harbor Perspect Med. 2021;11(2):a038984.CrossRef
44.
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some Invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14.PubMedPubMedCentralCrossRef
45.
Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8.PubMedPubMedCentralCrossRef
46.
Burgess S, Bowden J, Fall T, Ingelsson E, Thompson SG. Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants. Epidemiol (Cambridge Mass). 2017;28(1):30–42.CrossRef
47.
48.
Narasimhan PB, Marcovecchio P, Hamers AAJ, Hedrick CC. Nonclassical monocytes in Health and Disease. Annu Rev Immunol. 2019;37:439–56.PubMedCrossRef
49.
50.
Zhang C, Li T, Yin S, Gao M, He H, Li Y, et al. Monocytes deposit migrasomes to promote embryonic angiogenesis. Nat Cell Biol. 2022;24(12):1726–38.PubMedCrossRef
51.
Hanna RN, Cekic C, Sag D, Tacke R, Thomas GD, Nowyhed H, et al. Patrolling monocytes control tumor metastasis to the lung. Volume 350. New York, NY): Science; 2015. pp. 985–90. 6263.
52.
53.
Riemann D, Turzer S, Ganchev G, Schütte W, Seliger B, Möller M. Monitoring blood Immune cells in patients with Advanced Small Cell Lung Cancer undergoing a combined Immune Checkpoint Inhibitor/Chemotherapy. Biomolecules. 2023;13(2):190.PubMedPubMedCentralCrossRef
54.
Finotti G, Pietronigro E, Balanzin C, Lonardi S, Constantin G, Chao MP, et al. Slan + monocytes kill Cancer cells coated in therapeutic antibody by Trogoptosis. Cancer Immunol Res. 2023;11(11):1538–52.PubMedCrossRef
55.
Vermi W, Micheletti A, Finotti G, Tecchio C, Calzetti F, Costa S, et al. Slan + monocytes and macrophages Mediate CD20-Dependent B-cell lymphoma elimination via ADCC and ADCP. Cancer Res. 2018;78(13):3544–59.PubMedCrossRef
56.
Zhou J, Min Z, Zhang D, Wang W, Marincola F, Wang X. Enhanced frequency and potential mechanism of B regulatory cells in patients with lung cancer. J Transl Med. 2014;12:304.PubMedPubMedCentralCrossRef
57.
Hasan MM, Thompson-Snipes L, Klintmalm G, Demetris AJ, O’Leary J, Oh S et al. CD24hiCD38hi and CD24hiCD27 + Human Regulatory B Cells Display Common and Distinct Functional Characteristics. Journal of Immunology (Baltimore, Md: 1950). 2019;203(8):2110–20.
58.
Richardson JR, Schöllhorn A, Gouttefangeas C, Schuhmacher J. CD4 + T cells: Multitasking cells in the duty of Cancer Immunotherapy. Cancers. 2021;13(4):596.PubMedPubMedCentralCrossRef
59.
Tay RE, Richardson EK, Toh HC. Revisiting the role of CD4 + T cells in cancer immunotherapy-new insights into old paradigms. Cancer Gene Ther. 2021;28(1–2):5–17.PubMedCrossRef
60.
Speiser DE, Chijioke O, Schaeuble K, Münz C. CD4 + T cells in cancer. Nat Cancer. 2023;4(3):317–29.PubMedCrossRef
61.
Kagamu H, Kitano S, Yamaguchi O, Yoshimura K, Horimoto K, Kitazawa M, et al. CD4 + T-cell immunity in the peripheral blood correlates with response to Anti-PD-1 therapy. Cancer Immunol Res. 2020;8(3):334–44.PubMedCrossRef
62.
63.
Gao Y, Yang J, Cai Y, Fu S, Zhang N, Fu X, et al. IFN-γ-mediated inhibition of lung cancer correlates with PD-L1 expression and is regulated by PI3K-AKT signaling. Int J Cancer. 2018;143(4):931–43.PubMedCrossRef
64.
Aihara F, Wang Y, Belkina AC, Fearns R, Mizgerd JP, Feng F et al. Diversity of B Cell Populations and Ig Repertoire in Human Lungs. Journal of Immunology (Baltimore, Md: 1950). 2023;211(3):486–96.
65.
Weller S, Descatoire M. [IgM + IgD + CD27 + B cells in human: an essential role in the protection against encapsulated bacteria]. Med Sciences: M/S. 2015;31(6–7):647–53.
Metadata
Title
Assessing the causal relationship between 731 immunophenotypes and the risk of lung cancer: a bidirectional mendelian randomization study
Authors
Ming Xu
Chengkai Li
Liyan Xiang
Siyue Chen
Lin Chen
Gongxia Ling
Yanqing Hu
Lan Yang
Xiang Yuan
Xiaodong Xia
Hailin Zhang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-12014-1

Other articles of this Issue 1/2024

BMC Cancer 1/2024 Go to the issue

Research

Deep learning-assisted diagnosis of benign and malignant parotid tumors based on ultrasound: a retrospective study

Research

Characteristics of patients with recurrent retinoblastoma: a survival analysis

Research

Health-related risk behaviors among U.S. childhood cancer survivors: a nationwide estimate

Research

Ferroptosis-related lncRNA NRAV affects the prognosis of hepatocellular carcinoma via the miR-375-3P/SLC7A11 axis

Research

Survival analysis of Sudanese oral squamous cell carcinoma patients with field of cancerization

Research

Knockdown of NCAPD3 inhibits the tumorigenesis of non-small cell lung cancer by regulation of the PI3K/Akt pathway
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits