Accumulation of Plasmacytoid Dendritic Cell is Associated with a Treatment Response to DNA-damaging Treatment and Favorable Prognosis in Lung Adenocarcinoma

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Jul 12

PMID 37435086

Authors

Yoon Jin Cha

Eun Young Kim

Yong Jun Choi

Chi Young Kim

Min Kyung Park

Yoon Soo Chang

Affiliations

Soon will be listed here.

Abstract

Introduction: Favorable responses to the treatment including immune checkpoint inhibitors (ICIs) have been consistently reported in lung cancer with smoking history. As the tumor microenvironment (TME) may be involved in the treatment response to ICIs, we aimed to investigate the TME of lung cancer with different smoking status.

Methods: Lung adenocarcinoma (LUAD) tissue (Tu) and adjacent normal-appearing lung tissue (NL) from current and never smokers were investigated by single-cell RNA sequencing and immunofluorescence and immunohistochemical staining. The clinical implications of identified biomarkers were validated using open-source datasets.

Results: The lungs of smokers had an increased proportion of innate immune cells in NL tissues, whereas Tu tissues had a lower proportion of these cells than those of non-smokers. Monocyte-derived macrophages (mono-Mc), CD163-LGMN macrophages, monocyte-derived dendritic cells (DCs), and plasmacytoid DCs (pDCs) were significantly enriched in smokers' Tu. Among these clusters, pDCs, specifically enriched in the Tu of smokers. The expression of representative pDC markers, leukocyte immunoglobulin-like receptor A4 (LILRA4) and Toll-like receptor 9 (TLR9), was increased in the stromal cells of LUAD in patients with a smoking history. In an animal model of lung cancer, ionizing radiation induced robust TLR9 expressing immune cells in peritumoral area. Survival analysis using a TCGA-LUAD dataset indicated that patients overexpressing pDC markers exhibited superior clinical outcomes to age-, sex-, and smoking-matched control groups. Top 25% patients with high TLR9 expression exhibited significantly higher tumor mutational burden than that of low TLR9 expression group (bottom 25% patients) (5.81 mutations/Mb vs 4.36 mutations/Mb; = 0.0059, Welch's two-sample -test).

Conclusion: There is an increased pDC in the TME of smokers' lung cancer, and the response of pDC to DNA damaging treatment would lead a conducive environment to ICIs containing regimens. These findings suggest that R&D that induces an increase in the activated pDC population is continuously required to enhance therapeutic effectiveness of ICIs-containing therapies in lung cancer.

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References

Kim J, Ha H, Park J, Cho J, Lim J, Lee M . Association of Smoking Status with Efficacy of First-line Immune Checkpoint Inhibitors in Advanced Non-small Cell Lung Cancers: A Systematic Review and Meta-analysis. J Cancer. 2022; 13(2):364-372. PMC: 8771515. DOI: 10.7150/jca.65374. View

Jegouzo S, Feinberg H, Dungarwalla T, Drickamer K, Weis W, Taylor M . A Novel Mechanism for Binding of Galactose-terminated Glycans by the C-type Carbohydrate Recognition Domain in Blood Dendritic Cell Antigen 2. J Biol Chem. 2015; 290(27):16759-71. PMC: 4505424. DOI: 10.1074/jbc.M115.660613. View

Kim E, Cha Y, Lee S, Jeong S, Choi Y, Moon D . Early lung carcinogenesis and tumor microenvironment observed by single-cell transcriptome analysis. Transl Oncol. 2021; 15(1):101277. PMC: 8605359. DOI: 10.1016/j.tranon.2021.101277. View

Reck M, Rodriguez-Abreu D, Robinson A, Hui R, Csoszi T, Fulop A . Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375(19):1823-1833. DOI: 10.1056/NEJMoa1606774. View

Chakfe N, Ohana M . Commentary on "MRI-derived arterial peak flow in peripheral arterial disease: towards a standardized measurement". Eur J Vasc Endovasc Surg. 2014; 48(2):193. DOI: 10.1016/j.ejvs.2014.05.010. View

Dai L, Jin B, Liu T, Chen J, Li G, Dang J . The effect of smoking status on efficacy of immune checkpoint inhibitors in metastatic non-small cell lung cancer: A systematic review and meta-analysis. EClinicalMedicine. 2021; 38:100990. PMC: 8413256. DOI: 10.1016/j.eclinm.2021.100990. View

Borghaei H, Paz-Ares L, Horn L, Spigel D, Steins M, Ready N . Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015; 373(17):1627-39. PMC: 5705936. DOI: 10.1056/NEJMoa1507643. View

Zhang T, Joubert P, Ansari-Pour N, Zhao W, Hoang P, Lokanga R . Genomic and evolutionary classification of lung cancer in never smokers. Nat Genet. 2021; 53(9):1348-1359. PMC: 8432745. DOI: 10.1038/s41588-021-00920-0. View

Paez J, Janne P, Lee J, Tracy S, Greulich H, Gabriel S . EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304(5676):1497-500. DOI: 10.1126/science.1099314. View

10.

Hellmann M, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim S, Carcereny Costa E . Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2019; 381(21):2020-2031. DOI: 10.1056/NEJMoa1910231. View

11.

Reizis B . Plasmacytoid Dendritic Cells: Development, Regulation, and Function. Immunity. 2019; 50(1):37-50. PMC: 6342491. DOI: 10.1016/j.immuni.2018.12.027. View

12.

Lu N, Cidlowski J . Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol Cell. 2005; 18(3):331-42. DOI: 10.1016/j.molcel.2005.03.025. View

13.

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

14.

Wculek S, Cueto F, Mujal A, Melero I, Krummel M, Sancho D . Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2019; 20(1):7-24. DOI: 10.1038/s41577-019-0210-z. View

15.

Liu C, Lou Y, Lizee G, Qin H, Liu S, Rabinovich B . Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest. 2008; 118(3):1165-75. PMC: 2230660. DOI: 10.1172/JCI33583. View

16.

Rizvi N, Hellmann M, Snyder A, Kvistborg P, Makarov V, Havel J . Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348(6230):124-8. PMC: 4993154. DOI: 10.1126/science.aaa1348. View

17.

Gou L, Niu F, Wu Y, Zhong W . Differences in driver genes between smoking-related and non-smoking-related lung cancer in the Chinese population. Cancer. 2015; 121 Suppl 17:3069-79. DOI: 10.1002/cncr.29531. View

18.

Perrot I, Blanchard D, Freymond N, Isaac S, Guibert B, Pacheco Y . Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J Immunol. 2007; 178(5):2763-9. DOI: 10.4049/jimmunol.178.5.2763. View

19.

Sun Y, Yang Q, Shen J, Wei T, Shen W, Zhang N . The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer. Front Cell Dev Biol. 2021; 9:745859. PMC: 8512705. DOI: 10.3389/fcell.2021.745859. View

20.

Shi W, Li X, Porter J, Ostrodi D, Yang B, Li J . Level of plasmacytoid dendritic cells is increased in non-small cell lung carcinoma. Tumour Biol. 2013; 35(3):2247-52. DOI: 10.1007/s13277-013-1297-7. View