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Open Access 01-11-2024 | Lung Cancer | Research

Immunogenomic features of radiologically distinctive nodules in multiple primary lung cancer

Authors: Mei-Cheng Chen, Hao-Shuai Yang, Zhi Dong, Lu-Jie Li, Xiang-Min Li, Hong-He Luo, Qiong Li, Ying Zhu

Published in: Cancer Immunology, Immunotherapy | Issue 11/2024

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Abstract

Objectives

To provide molecular and immunological attributes mechanistic insights for the management of radiologically distinctive multiple primary lung cancer (MPLC).

Methods

The Bulk RNA-seq data of MPLC were obtained from our center. The Bulk RNA-seq data and CT images of patients with single primary lung cancer (SPLC) were obtained from GSE103584. Immune infiltration algorithms were performed to investigate the disparities in the immunological microenvironment between the two groups. Single-cell gene analysis was used to explore immune cells composition and communication relationships between cells in MPLC.

Results

In MPLC, 11 pure ground-glass opacity nodules (pGGN) and 10 mixed GGN (mGGN) were identified, while in SPLC, the numbers were 18 pGGN and 22 mGGN, respectively. In MPLC, compared to pGGN, mGGN demonstrated a significantly elevated infiltration of CD8+ T cells. Single-cell gene analysis demonstrated that CD8+ T cells play a central role in the signaling among immune cells in MPLC. The transcription factors including MAFG, RUNX3, and TBX21 may play pivotal roles in regulation of CD8+ T cells. Notably, compared to SPLC nodules for both mGGN and pGGN, MPLC nodules demonstrated a significantly elevated degree of tumor-infiltrating immune cells, with this difference being particularly pronounced in mGGN. There was a positive correlation between the proportion of immune cells and consolidation/tumor ratio (CTR).

Conclusions

Our findings provided a comprehensive description about the difference in the immune microenvironment between pGGN and mGGN in early-stage MPLC, as well as between MPLC and SPLC for both mGGN and pGGN. The findings may provide evidence for the design of immunotherapeutic strategies for MPLC.
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Literature
1.
go back to reference Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics. CA: a Cancer J Clin 72(1):7–33 Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics. CA: a Cancer J Clin 72(1):7–33
2.
go back to reference Martini N, Melamed MR (1975) Multiple primary lung cancers. J Thorac Cardiovasc Surg 70(4):606–612CrossRefPubMed Martini N, Melamed MR (1975) Multiple primary lung cancers. J Thorac Cardiovasc Surg 70(4):606–612CrossRefPubMed
4.
go back to reference Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD (2016) The IASLC Lung Cancer Staging Project: Background Data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thoracic Oncology 11(5):651–665. https://doi.org/10.1016/j.jtho.2016.01.025CrossRef Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD (2016) The IASLC Lung Cancer Staging Project: Background Data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thoracic Oncology 11(5):651–665. https://​doi.​org/​10.​1016/​j.​jtho.​2016.​01.​025CrossRef
5.
go back to reference Chen K, Chen W, Cai J, Yang F, Lou F, Wang X et al (2018) Favorable prognosis and high discrepancy of genetic features in surgical patients with multiple primary lung cancers. J Thorac Cardiovasc Surg 155(1):371–379CrossRefPubMed Chen K, Chen W, Cai J, Yang F, Lou F, Wang X et al (2018) Favorable prognosis and high discrepancy of genetic features in surgical patients with multiple primary lung cancers. J Thorac Cardiovasc Surg 155(1):371–379CrossRefPubMed
6.
go back to reference Vazquez M, Carter D, Brambilla E, Gazdar A, Noguchi M, Travis WD et al (2009) Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications. Lung Cancer 64(2):148–154CrossRefPubMed Vazquez M, Carter D, Brambilla E, Gazdar A, Noguchi M, Travis WD et al (2009) Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications. Lung Cancer 64(2):148–154CrossRefPubMed
8.
go back to reference Hattori A, Matsunaga T, Hayashi T, Takamochi K, Oh S, Suzuki K (2017) Prognostic impact of the findings on thin-section computed tomography in patients with subcentimeter non-small cell lung cancer. J Thorac Oncol 12(6):954–962CrossRefPubMed Hattori A, Matsunaga T, Hayashi T, Takamochi K, Oh S, Suzuki K (2017) Prognostic impact of the findings on thin-section computed tomography in patients with subcentimeter non-small cell lung cancer. J Thorac Oncol 12(6):954–962CrossRefPubMed
9.
go back to reference Shimada Y, Saji H, Otani K, Maehara S, Maeda J, Yoshida K et al (2015) Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions. Lung Cancer 88(2):174–180CrossRefPubMed Shimada Y, Saji H, Otani K, Maehara S, Maeda J, Yoshida K et al (2015) Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions. Lung Cancer 88(2):174–180CrossRefPubMed
10.
go back to reference Zhang Y, Fu F, Chen H (2020) Management of ground-glass opacities in the lung cancer spectrum. Ann Thorac Surg 110(6):1796–1804CrossRefPubMed Zhang Y, Fu F, Chen H (2020) Management of ground-glass opacities in the lung cancer spectrum. Ann Thorac Surg 110(6):1796–1804CrossRefPubMed
11.
go back to reference Asamura H, Hishida T, Suzuki K, Koike T, Nakamura K, Kusumoto M et al (2013) Radiographically determined noninvasive adenocarcinoma of the lung: survival outcomes of Japan clinical oncology group 0201. J Thorac Cardiovasc Surg 146(1):24–30CrossRefPubMed Asamura H, Hishida T, Suzuki K, Koike T, Nakamura K, Kusumoto M et al (2013) Radiographically determined noninvasive adenocarcinoma of the lung: survival outcomes of Japan clinical oncology group 0201. J Thorac Cardiovasc Surg 146(1):24–30CrossRefPubMed
12.
go back to reference Sun F, Huang Y, Yang X, Zhan C, Xi J, Lin Z et al (2020) Solid component ratio influences prognosis of GGO-featured IA stage invasive lung adenocarcinoma. Cancer Imaging: official Pub Int Cancer Imaging Soc 20(1):87CrossRef Sun F, Huang Y, Yang X, Zhan C, Xi J, Lin Z et al (2020) Solid component ratio influences prognosis of GGO-featured IA stage invasive lung adenocarcinoma. Cancer Imaging: official Pub Int Cancer Imaging Soc 20(1):87CrossRef
13.
go back to reference Hattori A, Takamochi K, Oh S, Suzuki K (2020) Prognostic classification of multiple primary lung cancers based on a ground-glass opacity component. Ann Thorac Surg 109(2):420–427CrossRefPubMed Hattori A, Takamochi K, Oh S, Suzuki K (2020) Prognostic classification of multiple primary lung cancers based on a ground-glass opacity component. Ann Thorac Surg 109(2):420–427CrossRefPubMed
14.
go back to reference Kobayashi Y, Mitsudomi T, Sakao Y, Yatabe Y (2015) Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules: the differences between nodules with and without growth. Ann Oncol 26(1):156–161CrossRefPubMed Kobayashi Y, Mitsudomi T, Sakao Y, Yatabe Y (2015) Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules: the differences between nodules with and without growth. Ann Oncol 26(1):156–161CrossRefPubMed
15.
go back to reference Chen K, Bai J, Reuben A, Zhao H, Kang G, Zhang C et al (2021) Multiomics analysis reveals distinct immunogenomic features of lung cancer with ground-glass opacity. Am J Respir Crit Care Med 204(10):1180–1192CrossRefPubMedPubMedCentral Chen K, Bai J, Reuben A, Zhao H, Kang G, Zhang C et al (2021) Multiomics analysis reveals distinct immunogenomic features of lung cancer with ground-glass opacity. Am J Respir Crit Care Med 204(10):1180–1192CrossRefPubMedPubMedCentral
16.
go back to reference Goodwin D, Rathi V, Conron M, Wright GM (2021) Genomic and clinical significance of multiple primary lung cancers as determined by next-generation sequencing. J Thorac Oncol 16(7):1166–1175CrossRefPubMed Goodwin D, Rathi V, Conron M, Wright GM (2021) Genomic and clinical significance of multiple primary lung cancers as determined by next-generation sequencing. J Thorac Oncol 16(7):1166–1175CrossRefPubMed
17.
go back to reference Zhang C, Yin K, Liu SY, Yan LX, Su J, Wu YL et al (2021) Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy. J Immunother Cancer 9(4):e002312CrossRefPubMedPubMedCentral Zhang C, Yin K, Liu SY, Yan LX, Su J, Wu YL et al (2021) Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy. J Immunother Cancer 9(4):e002312CrossRefPubMedPubMedCentral
18.
go back to reference Cheng B, Li C, Li J, Gong L, Liang P, Chen Y et al (2024) The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions: insights from a single-arm, phase II trial. Signal Transduct Targeted Ther 9(1):93CrossRef Cheng B, Li C, Li J, Gong L, Liang P, Chen Y et al (2024) The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions: insights from a single-arm, phase II trial. Signal Transduct Targeted Ther 9(1):93CrossRef
19.
go back to reference Li Y, Li X, Li H, Zhao Y, Liu Z, Sun K et al (2020) Genomic characterisation of pulmonary subsolid nodules: mutational landscape and radiological features. European Respir J 55(2):1901409CrossRef Li Y, Li X, Li H, Zhao Y, Liu Z, Sun K et al (2020) Genomic characterisation of pulmonary subsolid nodules: mutational landscape and radiological features. European Respir J 55(2):1901409CrossRef
20.
go back to reference Zeng D, Ye Z, Shen R, Yu G, Wu J, Xiong Y et al (2021) IOBR: Multi-omics immuno-oncology biological research to decode tumor microenvironment and signatures. Front Immunol 12:687975CrossRefPubMedPubMedCentral Zeng D, Ye Z, Shen R, Yu G, Wu J, Xiong Y et al (2021) IOBR: Multi-omics immuno-oncology biological research to decode tumor microenvironment and signatures. Front Immunol 12:687975CrossRefPubMedPubMedCentral
21.
go back to reference Shi Y, Fan S, Wu M, Zuo Z, Li X, Jiang L et al (2019) YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun 10(1):4892CrossRefPubMedPubMedCentral Shi Y, Fan S, Wu M, Zuo Z, Li X, Jiang L et al (2019) YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun 10(1):4892CrossRefPubMedPubMedCentral
22.
go back to reference Mittal V (2018) Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol 13:395–412CrossRefPubMed Mittal V (2018) Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol 13:395–412CrossRefPubMed
23.
go back to reference Multhaupt HA, Leitinger B, Gullberg D, Couchman JR (2016) Extracellular matrix component signaling in cancer. Adv Drug Deliv Rev 97:28–40CrossRefPubMed Multhaupt HA, Leitinger B, Gullberg D, Couchman JR (2016) Extracellular matrix component signaling in cancer. Adv Drug Deliv Rev 97:28–40CrossRefPubMed
24.
go back to reference Wu S, Li D, Chen J, Chen W, Ren F (2021) Tailing effect of PD-1 antibody results in the eradication of unresectable multiple primary lung cancer presenting as ground-glass opacities: a case report. Ann Palliat Med 10(1):778–784CrossRefPubMed Wu S, Li D, Chen J, Chen W, Ren F (2021) Tailing effect of PD-1 antibody results in the eradication of unresectable multiple primary lung cancer presenting as ground-glass opacities: a case report. Ann Palliat Med 10(1):778–784CrossRefPubMed
25.
go back to reference Wang M, Herbst RS, Boshoff C (2021) Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med 27(8):1345–1356CrossRefPubMed Wang M, Herbst RS, Boshoff C (2021) Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med 27(8):1345–1356CrossRefPubMed
26.
go back to reference Locati M, Curtale G, Mantovani A (2020) Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol 15:123–147CrossRefPubMed Locati M, Curtale G, Mantovani A (2020) Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol 15:123–147CrossRefPubMed
27.
go back to reference Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555CrossRefPubMed Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555CrossRefPubMed
28.
go back to reference Duchemann B, Naigeon M, Auclin E, Ferrara R, Cassard L, Jouniaux J-M et al (2022) CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers. J Immunother Cancer 10(2):e004012CrossRefPubMedPubMedCentral Duchemann B, Naigeon M, Auclin E, Ferrara R, Cassard L, Jouniaux J-M et al (2022) CD8+PD-1+ to CD4+PD-1+ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers. J Immunother Cancer 10(2):e004012CrossRefPubMedPubMedCentral
29.
go back to reference Li F, Li C, Cai X, Xie Z, Zhou L, Cheng B et al (2021) The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: a systematic review and meta-analysis. Clin Med 41:101134 Li F, Li C, Cai X, Xie Z, Zhou L, Cheng B et al (2021) The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: a systematic review and meta-analysis. Clin Med 41:101134
30.
go back to reference Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM (2020) B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol 20(5):294–307CrossRefPubMed Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM (2020) B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol 20(5):294–307CrossRefPubMed
31.
go back to reference Yang W, Feng B, Meng Y, Wang J, Geng B, Cui Q et al (2019) FAM3C-YY1 axis is essential for TGFbeta-promoted proliferation and migration of human breast cancer MDA-MB-231 cells via the activation of HSF1. J Cell Mol Med 23(5):3464–3475CrossRefPubMedPubMedCentral Yang W, Feng B, Meng Y, Wang J, Geng B, Cui Q et al (2019) FAM3C-YY1 axis is essential for TGFbeta-promoted proliferation and migration of human breast cancer MDA-MB-231 cells via the activation of HSF1. J Cell Mol Med 23(5):3464–3475CrossRefPubMedPubMedCentral
32.
go back to reference Shi M, Duan G, Nie S, Shen S, Zou X (2018) Elevated FAM3C promotes cell epithelial-mesenchymal transition and cell migration in gastric cancer. Onco Targets Ther 11:8491–8505CrossRefPubMedPubMedCentral Shi M, Duan G, Nie S, Shen S, Zou X (2018) Elevated FAM3C promotes cell epithelial-mesenchymal transition and cell migration in gastric cancer. Onco Targets Ther 11:8491–8505CrossRefPubMedPubMedCentral
33.
go back to reference Jansson AM, Csiszar A, Maier J, Nystrom AC, Ax E, Johansson P et al (2017) The interleukin-like epithelial-mesenchymal transition inducer ILEI exhibits a non-interleukin-like fold and is active as a domain-swapped dimer. J Biol Chem 292(37):15501–15511CrossRefPubMedPubMedCentral Jansson AM, Csiszar A, Maier J, Nystrom AC, Ax E, Johansson P et al (2017) The interleukin-like epithelial-mesenchymal transition inducer ILEI exhibits a non-interleukin-like fold and is active as a domain-swapped dimer. J Biol Chem 292(37):15501–15511CrossRefPubMedPubMedCentral
34.
go back to reference Thuya WL, Kong LR, Syn NL, Ding LW, Cheow ESH, Wong RTX et al (2023) FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites. Theranostics 13(2):621–638CrossRefPubMedPubMedCentral Thuya WL, Kong LR, Syn NL, Ding LW, Cheow ESH, Wong RTX et al (2023) FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites. Theranostics 13(2):621–638CrossRefPubMedPubMedCentral
35.
go back to reference Fan W, Cao D, Yang B, Wang J, Li X, Kitka D et al (2024) Hepatic prohibitin 1 and methionine adenosyltransferase alpha1 defend against primary and secondary liver cancer metastasis. J Hepatol 80(3):443–453CrossRefPubMed Fan W, Cao D, Yang B, Wang J, Li X, Kitka D et al (2024) Hepatic prohibitin 1 and methionine adenosyltransferase alpha1 defend against primary and secondary liver cancer metastasis. J Hepatol 80(3):443–453CrossRefPubMed
36.
go back to reference Jia YC, Wang JY, Liu YY, Li B, Guo H, Zang AM (2019) LncRNA MAFG-AS1 facilitates the migration and invasion of NSCLC cell via sponging miR-339-5p from MMP15. Cell Biol Int 43(4):384–393CrossRefPubMed Jia YC, Wang JY, Liu YY, Li B, Guo H, Zang AM (2019) LncRNA MAFG-AS1 facilitates the migration and invasion of NSCLC cell via sponging miR-339-5p from MMP15. Cell Biol Int 43(4):384–393CrossRefPubMed
38.
go back to reference Wang G, Sun J, Zhang J, Zhu Q, Lu J, Gao S et al (2023) Single-cell transcriptional profiling uncovers the association between EOMES(+)CD8(+) T cells and acquired EGFR-TKI resistance. Drug Resistance Updates: Rev Comment Antimicrob Anticancer Chemother 66:100910CrossRef Wang G, Sun J, Zhang J, Zhu Q, Lu J, Gao S et al (2023) Single-cell transcriptional profiling uncovers the association between EOMES(+)CD8(+) T cells and acquired EGFR-TKI resistance. Drug Resistance Updates: Rev Comment Antimicrob Anticancer Chemother 66:100910CrossRef
39.
go back to reference Xiao ZJ, Liu J, Wang SQ, Zhu Y, Gao XY, Tin VP et al (2017) NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma. Elife 6:e26733CrossRefPubMedPubMedCentral Xiao ZJ, Liu J, Wang SQ, Zhu Y, Gao XY, Tin VP et al (2017) NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma. Elife 6:e26733CrossRefPubMedPubMedCentral
Metadata
Title
Immunogenomic features of radiologically distinctive nodules in multiple primary lung cancer
Authors
Mei-Cheng Chen
Hao-Shuai Yang
Zhi Dong
Lu-Jie Li
Xiang-Min Li
Hong-He Luo
Qiong Li
Ying Zhu
Publication date
01-11-2024
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 11/2024
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-024-03807-1

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