Patterns of immune infiltration in lung adenocarcinoma revealed a prognosis-associated microRNA–mast cells network

  • 55 Accesses


Immune infiltration of tumor microenvironment is an important determinant for immune response and outcomes. To investigate the diversity and clinical relevance of immune infiltration in lung adenocarcinoma (LUAD), we performed a comprehensive analysis using the bulk tumor transcriptomes. The prognosis significance for immune infiltration was systematically evaluated and sufficient immune infiltration was associated with better outcomes. Resting mast cells emerged as the most strongly associated with better overall survival (OS) and disease-free survival (DFS), whereas the activated mast cells were correlated with adverse survival. Immune infiltration-based classification exhibited clinical relevance and provided a close link between cancer cell-intrinsic genetic events and immune landscape. The immune infiltration–miRNA functional network analysis showed that the resting mast cell-associated miRNAs are mainly involved in the enrichment of development, mRNA metabolic process, myeloid cell differentiation, Wnt, calcium modulating, interferon, p53 pathways. Additionally, we found one promoter (miR-30a) and one suppressor (miR-550a) of resting mast cells. Coupling the detailed analyses of the cellular immune infiltration and the implicated modulation role of miRNAs provides novel type of candidates for LUAD immunotherapy.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Data availability

All omics data and clinicopathological parameter data were downloaded from the TCGA data portal (


  1. 1.

    Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD. Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e1S–29S.

  2. 2.

    Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32:605–44.

  3. 3.

    Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.

  4. 4.

    Bremnes RM, Al-Shibli K, Donnem T, et al. The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer. J Thorac Oncol. 2011;6:824–33.

  5. 5.

    Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13:273–90.

  6. 6.

    Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73.

  7. 7.

    Reynders K, De Ruysscher D. Tumor infiltrating lymphocytes in lung cancer: a new prognostic parameter. J Thorac Dis. 2016;8:E833–5.

  8. 8.

    Vasaturo A, Halilovic A, Bol KF, et al. T cell landscape in a primary melanoma predicts the survival of patients with metastatic disease after their treatment with dendritic cell vaccines. Cancer Res. 2016;76:3496–506.

  9. 9.

    Chevrier S, Levine JH, Zanotelli VRT, et al. An immune atlas of clear cell renal cell carcinoma. Cell. 2017;169(736–49):e18.

  10. 10.

    Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.

  11. 11.

    Ganesan AP, Johansson M, Ruffell B, et al. Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol. 2013;191:2009–17.

  12. 12.

    Platonova S, Cherfils-Vicini J, Damotte D, et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 2011;71:5412–22.

  13. 13.

    Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.

  14. 14.

    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

  15. 15.

    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

  16. 16.

    Kao SC, Cheng YY, Williams M, et al. Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma. J Thorac Oncol. 2017;12:1421–33.

  17. 17.

    Chen L, Gibbons DL, Goswami S, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014;5:5241.

  18. 18.

    Zhao L, Yu H, Yi S, et al. The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer. Oncotarget. 2016;7:45370–84.

  19. 19.

    Li QJ, Chau J, Ebert PJ, et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell. 2007;129:147–61.

  20. 20.

    Ueda R, Kohanbash G, Sasaki K, et al. Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1. Proc Natl Acad Sci USA. 2009;106:10746–51.

  21. 21.

    Jin P, Han TH, Ren J, et al. Molecular signatures of maturing dendritic cells: implications for testing the quality of dendritic cell therapies. J Transl Med. 2010;8:4.

  22. 22.

    Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.

  23. 23.

    Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. eLife. 2015.

  24. 24.

    Yang JH, Li JH, Shao P, Zhou H, Chen YQ, Qu LH. starBase: a database for exploring microRNA-mRNA interaction maps from Argonaute CLIP-Seq and Degradome-Seq data. Nucleic Acids Res. 2011;39:D202–9.

  25. 25.

    Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.

  26. 26.

    Tripathi S, Pohl MO, Zhou Y, et al. Meta- and Orthogonal Integration of Influenza “OMICs” Data Defines a Role for UBR4 in Virus Budding. Cell Host Microbe. 2015;18:723–35.

  27. 27.

    Carter SL, Cibulskis K, Helman E, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30:413–21.

  28. 28.

    Yoshihara K, Shahmoradgoli M, Martinez E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.

  29. 29.

    Senbabaoglu Y, Gejman RS, Winer AG, et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol. 2016;17:231.

  30. 30.

    Wellenstein MD, de Visser KE. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity. 2018;48:399–416.

  31. 31.

    Liao W, Overman MJ, Boutin AT, et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell. 2019;35(559–72):e7.

  32. 32.

    Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61.

  33. 33.

    Lu LF, Liston A. MicroRNA in the immune system, microRNA as an immune system. Immunology. 2009;127:291–8.

  34. 34.

    Mehta A, Baltimore D. MicroRNAs as regulatory elements in immune system logic. Nat Rev Immunol. 2016;16:279–94.

  35. 35.

    Dudda JC, Salaun B, Ji Y, et al. MicroRNA-155 is required for effector CD8+ T cell responses to virus infection and cancer. Immunity. 2013;38:742–53.

  36. 36.

    Sun Y, Oravecz-Wilson K, Mathewson N, et al. Mature T cell responses are controlled by microRNA-142. J Clin Investig. 2015;125:2825–40.

  37. 37.

    Geissler K, Fornara P, Lautenschlager C, Holzhausen HJ, Seliger B, Riemann D. Immune signature of tumor infiltrating immune cells in renal cancer. Oncoimmunology. 2015;4:e985082.

  38. 38.

    Herrero-Vicent C, Guerrero A, Gavila J, et al. Predictive and prognostic impact of tumour-infiltrating lymphocytes in triple-negative breast cancer treated with neoadjuvant chemotherapy. Ecancermedicalscience. 2017;11:759.

  39. 39.

    Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27:109–18.

  40. 40.

    Bluestone JA, Khattri R, Sciammas R, Sperling AI. TCR gamma delta cells: a specialized T-cell subset in the immune system. Annu Rev Cell Dev Biol. 1995;11:307–53.

  41. 41.

    Toro JR, Liewehr DJ, Pabby N, et al. Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T cell lymphoma. Blood. 2003;101:3407–12.

  42. 42.

    Marichal T, Tsai M, Galli SJ. Mast cells: potential positive and negative roles in tumor biology. Cancer Immunol Res. 2013;1:269–79.

  43. 43.

    Chang DZ, Ma Y, Ji B, et al. Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2011;17:7015–23 (An official journal of the American Association for Cancer Research).

  44. 44.

    Ma Y, Hwang RF, Logsdon CD, Ullrich SE. Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer. Cancer Res. 2013;73:3927–37.

  45. 45.

    Dundar E, Oner U, Peker BC, Metintas M, Isiksoy S, Ak G. The significance and relationship between mast cells and tumour angiogenesis in non-small cell lung carcinoma. J Int Med Res. 2008;36:88–95.

  46. 46.

    Detoraki A, Staiano RI, Granata F, et al. Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects. J Allergy Clin Immunol. 2009;123:1142–9.

  47. 47.

    Giannou AD, Marazioti A, Spella M, et al. Mast cells mediate malignant pleural effusion formation. J Clin Investig. 2015;125:2317–34.

  48. 48.

    Huang B, Lei Z, Zhang GM, et al. SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood. 2008;112:1269–79.

  49. 49.

    Prevete N, Staiano RI, Granata F, et al. Expression and function of Angiopoietins and their tie receptors in human basophils and mast cells. J Biol Regul Homeost Agents. 2013;27:827–39.

  50. 50.

    Visciano C, Liotti F, Prevete N, et al. Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8-Akt-Slug pathway. Oncogene. 2015;34:5175–86.

  51. 51.

    Samoszuk M, Corwin MA. Acceleration of tumor growth and peri-tumoral blood clotting by imatinib mesylate (Gleevec). Int J Cancer. 2003;106:647–52.

  52. 52.

    Ribatti D, Ennas MG, Vacca A, et al. Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest. 2003;33:420–5.

  53. 53.

    Hu E, Ding L, Miao H, et al. MiR-30a attenuates immunosuppressive functions of IL-1beta-elicited mesenchymal stem cells via targeting TAB 3. FEBS Lett. 2015;589:3899–907.

  54. 54.

    Gong J, Liu R, Zhuang R, et al. miR-30c-1* promotes natural killer cell cytotoxicity against human hepatoma cells by targeting the transcription factor HMBOX1. Cancer Sci. 2012;103:645–52.

  55. 55.

    Khokhar A, Noorali S, Sheraz M, et al. Computational analysis to predict functional role of hsa-miR-3065-3p as an antiviral therapeutic agent for treatment of triple infections: HCV, HIV-1, and HBV. Libyan J Med. 2012;7:19774.

  56. 56.

    Noman MZ, Buart S, Romero P, et al. Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. Cancer Res. 2012;72:4629–41.

  57. 57.

    Muhlberg L, Kuhnemuth B, Costello E, et al. miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer. Oncoimmunology. 2016;5:e1160181.

  58. 58.

    Yang D, Meng X, Xue B, Liu N, Wang X, Zhu H. MiR-942 mediates hepatitis C virus-induced apoptosis via regulation of ISG12a. PLoS One. 2014;9:e94501.

  59. 59.

    Montoya MM, Maul J, Singh PB, et al. A distinct inhibitory function for miR-18a in Th17 cell differentiation. J Immunol. 2017;199:559–69.

Download references


The authors thank the contributors of the TCGA ( for sharing their data on open access.

Author information

YHX designed the study. YHX, CLW and XT prepared the figures. CLW and XT analyzed and interpreted the data. CLW and XT drafted the manuscript. All authors have read and approved the manuscript.

Correspondence to Yanhua Xu.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, C., Tang, X., Wang, J. et al. Patterns of immune infiltration in lung adenocarcinoma revealed a prognosis-associated microRNA–mast cells network. Human Cell 33, 205–219 (2020) doi:10.1007/s13577-019-00300-1

Download citation


  • Lung adenocarcinoma
  • Immune infiltration
  • Prognosis
  • Classification
  • Mast cells