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Tumor-infiltrating B cells: their role and application in anti-tumor immunity in lung cancer

Cellular & Molecular Immunology (2018) | Download Citation

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Abstract

Evidence indicates that lung cancer development is a complex process that involves interactions between tumor cells, stromal fibroblasts, and immune cells. Tumor-infiltrating immune cells play a significant role in the promotion or inhibition of tumor growth. As an integral component of the tumor microenvironment, tumor-infiltrating B lymphocytes (TIBs) exist in all stages of cancer and play important roles in shaping tumor development. Here, we review recent clinical and preclinical studies that outline the role of TIBs in lung cancer development, assess their prognostic significance, and explore the potential benefit of B cell-based immunotherapy for lung cancer treatment.

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References

  1. 1.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin. 67, 7–30 (2017).

  2. 2.

    Remark, R. et al. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am. J. Respir. Crit. Care. Med. 191, 377–390 (2015).

  3. 3.

    Kataki, A. et al. Tumor infiltrating lymphocytes and macrophages have a potential dual role in lung cancer by supporting both host-defense and tumor progression. J. Lab. Clin. Med. 140, 320–328 (2002).

  4. 4.

    Brambilla, E. et al. Prognostic effect of tumor lymphocytic infiltration in resectable non-small-cell lung cancer. J. Clin. Oncol. 34, 1223–1230 (2016).

  5. 5.

    Bremnes, R. M. et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J. Thorac. Oncol. 11, 789–800 (2016).

  6. 6.

    Schalper, K. A. et al. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J. Natl Cancer Inst. 107, dju435 (2015).

  7. 7.

    Marshall, E. A. et al. Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis. Mol. Cancer 15, 67 (2016).

  8. 8.

    Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

  9. 9.

    Zeltsman, M., Dozier, J., McGee, E., Ngai, D. & Adusumilli, P. S. CAR T-cell therapy for lung cancer and malignant pleural mesothelioma. Transl. Res. 187, 1–10 (2017).

  10. 10.

    Gottlin, E. B. et al. The association of intratumoral germinal centers with early-stage non-small cell lung cancer. J. Thorac. Oncol. 6, 1687–1690 (2011).

  11. 11.

    Dieu-Nosjean, M. C., Goc, J., Giraldo, N. A., Sautès-Fridman, C. & Fridman, W. H. Tertiary lymphoid structures in cancer and beyond. Trends Immunol. 35, 571–580 (2014).

  12. 12.

    Banat, G. A. et al. Immune and inflammatory cell composition of human lung cancer stroma. PLoS ONE 10, e0139073 (2015).

  13. 13.

    Kurebayashi, Y. et al. Comprehensive immune profiling of lung adenocarcinomas reveals four immunosubtypes with plasma cell subtype a negative indicator. Cancer Immunol. Res. 4, 234–247 (2016).

  14. 14.

    Siliņa, K., Rulle, U., Kalniņa, Z. & Line, A. Manipulation of tumour-infiltrating B cells and tertiary lymphoid structures: a novel anti-cancer treatment avenue? Cancer Immunol. Immunother. 63, 643–662 (2014).

  15. 15.

    Del Mar Valenzuela-Membrives, M. et al. Progressive changes in composition of lymphocytes in lung tissues from patients with non-small-cell lung cancer. Oncotarget 7, 71608–71619 (2016).

  16. 16.

    de Chaisemartin, L. et al. Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res. 71, 6391–6399 (2011).

  17. 17.

    Kawamata, N. et al. Expression of endothelia and lymphocyte adhesion molecules in bronchus-associated lymphoid tissue (BALT) in adult human lung. Respir. Res. 10, 97 (2009).

  18. 18.

    Wang, G. Z. et al. The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution. eLife 4, e09419 (2015).

  19. 19.

    Campa, M. J. et al. Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery. Cancer Immunol. Immunother. 65, 171–180 (2016).

  20. 20.

    Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).

  21. 21.

    Germain, C. et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am. J. Respir. Crit. Care. Med. 189, 832–844 (2014).

  22. 22.

    Dieu-Nosjean, M. C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26, 4410–4417 (2008).

  23. 23.

    Neyt, K., Perros, F., GeurtsvanKessel, C. H., Hammad, H. & Lambrecht, B. N. Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol. 33, 297–305 (2012).

  24. 24.

    Sautès-Fridman, C. et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front. Immunol. 7, 407 (2016).

  25. 25.

    Longerich, S., Basu, U., Alt, F. & Storb, U. AID in somatic hypermutation and class switch recombination. Curr. Opin. Immunol. 18, 164–174 (2006).

  26. 26.

    Mohr, E. et al. Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J. Immunol. 182, 2113–2123 (2009).

  27. 27.

    McDonald, K. G., McDonough, J. S. & Newberry, R. D. Adaptive immune responses are dispensable for isolated lymphoid follicle formation: antigen-naive, lymphotoxin-sufficient B lymphocytes drive the formation of mature isolated lymphoid follicles. J. Immunol. 174, 5720–5728 (2005).

  28. 28.

    Marchesi, F. et al. CXCL13 expression in the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles. Mucosal Immunol. 2, 486–494 (2009).

  29. 29.

    Litsiou, E. et al. CXCL13 production in B cells via Toll-like receptor/lymphotoxin receptor signaling is involved in lymphoid neogenesis in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care. Med. 187, 1194–1202 (2013).

  30. 30.

    Sautès-Fridman, C. et al. Tumor microenvironment is multifaceted. Cancer Metastas. Rev. 30, 13–25 (2011).

  31. 31.

    Schrama, D. et al. Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14, 111–121 (2001).

  32. 32.

    Schrama, D. et al. Immunological tumor destruction in a murine melanoma model by targeted LTalpha independent of secondary lymphoid tissue. Cancer Immunol. Immunother. 57, 85–95 (2008).

  33. 33.

    Andreu, P. et al. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell. 17, 121–134 (2010).

  34. 34.

    de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell. 7, 411–423 (2005).

  35. 35.

    Lohr, M. et al. The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer. Cancer Lett. 333, 222–228 (2013).

  36. 36.

    Mizukami, M. et al. Effect of IgG produced by tumor-infiltrating B lymphocytes on lung tumor growth. Anticancer. Res. 26, 1827–1831 (2006).

  37. 37.

    Foy, K. C. et al. Peptide vaccines and peptidomimetics of EGFR (HER-1) ligand binding domain inhibit cancer cell growth in vitro and in vivo. J. Immunol. 191, 217–227 (2013).

  38. 38.

    Mizukami, M. et al. Anti-tumor effect of antibody against a SEREX-defined antigen (UOEH-LC-1) on lung cancer xenotransplanted into severe combined immunodeficiency mice. Cancer Res. 67, 8351–8357 (2007).

  39. 39.

    Kinoshita, T. et al. Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer. Ann. Oncol. 27, 2117–2123 (2016).

  40. 40.

    Eerola, A. K., Soini, Y. & Pääkkö, P. Tumour infiltrating lymphocytes in relation to tumour angiogenesis, apoptosis and prognosis in patients with large cell lung carcinoma. Lung. Cancer 26, 73–83 (1999).

  41. 41.

    Bruno, T. C. et al. Antigen-presenting intratumoral B cells affect CD4+TIL phenotypes in non-small cell lung cancer patients. Cancer Immunol. Res 5, 898–907 (2017).

  42. 42.

    Jones, H. P., Wang, Y. C., Aldridge, B. & Weiss, J. M. Lung and splenic B cells facilitate diverse effects on in vitro measures of anti-tumor immune responses. Cancer Immun. 8, 4 (2008).

  43. 43.

    Yasuda, M. et al. Tumor-infiltrating B lymphocytes as a potential source of identifying tumor antigen in human lung cancer. Cancer Res. 62, 1751–1756 (2002).

  44. 44.

    Zhu, W. et al. A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+T cell receptor repertoire clonality. Oncoimmunology 4, e1051922 (2015).

  45. 45.

    Shi, J. Y. et al. Margin-infiltrating CD20(+) B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. Clin. Cancer Res. 19, 5994–6005 (2013).

  46. 46.

    Kemp, T. J., Moore, J. M. & Griffith, T. S. Human B cells express functional TRAIL/Apo-2 ligand after CpG-containing oligodeoxynucleotide stimulation. J. Immunol. 173, 892–899 (2004).

  47. 47.

    Lindner, S. et al. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells. Cancer Res. 73, 2468–2479 (2013).

  48. 48.

    Balkwill, F., Montfort, A. & Capasso, M. B regulatory cells in cancer. Trends Immunol. 34, 169–173 (2013).

  49. 49.

    Fremd, C., Schuetz, F., Sohn, C., Beckhove, P. & Domschke, C. B cell-regulated immune responses in tumor models and cancer patients. Oncoimmunology 2, e25443 (2013).

  50. 50.

    Schwartz, M., Zhang, Y. & Rosenblatt, J. D. B cell regulation of the anti-tumor response and role in carcinogenesis. J. Immunother. Cancer 4, 40 (2016).

  51. 51.

    Zhang, Y., Gallastegui, N. & Rosenblatt, J. D. Regulatory B cells in anti-tumor immunity. Int. Immunol. 27, 521–530 (2015).

  52. 52.

    Lizotte, P. H. et al. Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes. JCI Insight 1, e89014 (2016).

  53. 53.

    Sarvaria, A., Madrigal, J. A. & Saudemont, A. B cell regulation in cancer and anti-tumor immunity. Cell. Mol. Immunol. 14, 662–674 (2017).

  54. 54.

    Mauri, C. & Bosma, A. Immune regulatory function of B cells. Annu. Rev. Immunol. 30, 221–241 (2012).

  55. 55.

    Mion, F., Tonon, S., Valeri, V. & Pucillo, C. E. Message in a bottle from the tumor microenvironment: tumor-educated DCs instruct B cells to participate in immunosuppression. Cell. Mol. Immunol. 14, 730–732 (2017).

  56. 56.

    Cho, K. A. et al. Mesenchymal stem cells ameliorate B-cell-mediated immune responses and increase IL-10-expressing regulatory B cells in an EBI3-dependent manner. Cell. Mol. Immunol. 14, 895–908 (2017).

  57. 57.

    Zhou, J. et al. Enhanced frequency and potential mechanism of B regulatory cells in patients with lung cancer. J. Transl. Med. 12, 304 (2014).

  58. 58.

    Amrouche, K. & Jamin, C. Influence of drug molecules on regulatory B cells. Clin. Immunol. 184, 1–10 (2017).

  59. 59.

    Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015).

  60. 60.

    Affara, N. I. et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell. 25, 809–821 (2014).

  61. 61.

    Yang, C. et al. B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS. One. 8, e64159 (2013).

  62. 62.

    Olkhanud, P. B. et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+T cells to T-regulatory cells. Cancer Res. 71, 3505–3515 (2011).

  63. 63.

    Bodogai, M. et al. Immune suppressive and pro-metastatic functions of myeloid-derived suppressive cells rely upon education from tumor-associated B cells. Cancer Res. 75, 3456–3465 (2015).

  64. 64.

    Liu, J. et al. Aberrant frequency of IL-10-producing B cells and its association with Treg and MDSC cells in non small cell lung carcinoma patients. Hum. Immunol. 77, 84–89 (2016).

  65. 65.

    Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798–809 (2009).

  66. 66.

    Yang, C. et al. Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS ONE 8, e54029 (2013).

  67. 67.

    Zhang, C. et al. CD5 binds to interleukin-6 and induces a feed-forward loop with the transcription factor STAT3 in B cells to promote cancer. Immunity 44, 913–923 (2016).

  68. 68.

    Pelletier, M. P., Edwardes, M. D., Michel, R. P., Halwani, F. & Morin, J. E. Prognostic markers in resectable non-small cell lung cancer: a multivariate analysis. Can. J. Surg. 44, 180–188 (2001).

  69. 69.

    Al-Shibli, K. I. et al. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin. Cancer Res. 14, 5220–5227 (2008).

  70. 70.

    Hernández-Prieto, S. et al. A 50-gene signature is a novel scoring system for tumor-infiltrating immune cells with strong correlation with clinical outcome of stage I/II non-small cell lung cancer. Clin. Transl. Oncol. 17, 330–338 (2015).

  71. 71.

    Hald, S. M. et al. CD4/CD8 co-expression shows independent prognostic impact in resected non-small cell lung cancer patients treated with adjuvant radiotherapy. Lung Cancer 80, 209–215 (2013).

  72. 72.

    Suzuki, K. et al. Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor β2 (IL-12Rβ2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence. J. Clin. Oncol. 31, 490–498 (2013).

  73. 73.

    Eerola, A. K., Soini, Y. & Pääkkö, P. A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma. Clin. Cancer Res. 6, 1875–1881 (2000).

  74. 74.

    Faruki, H. et al. Lung adenocarcinoma and squamous cell carcinoma gene expression subtypes demonstrate significant differences in tumor immune landscape. J. Thorac. Oncol. 12, 943–953 (2017).

  75. 75.

    Schmidt, M. et al. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin κ C as a compatible prognostic marker in human solid tumors. Clin. Cancer Res. 18, 2695–2703 (2012).

  76. 76.

    Fujimoto, M. et al. Stromal plasma cells expressing immunoglobulin G4 subclass in non-small cell lung cancer. Hum. Pathol. 44, 1569–1576 (2013).

  77. 77.

    Al-Shibli, K. et al. The prognostic value of intraepithelial and stromal CD3-, CD117- and CD138-positive cells in non-small cell lung carcinoma. APMIS 118, 371–382 (2010).

  78. 78.

    Chiaruttini, G. et al. B cells and the humoral response in melanoma: the overlooked players of the tumor microenvironment. Oncoimmunology 6, e1294296 (2017).

  79. 79.

    Klotz, M. et al. Shift in the IgG subclass distribution in patients with lung cancer. Lung. Cancer 24, 25–30 (1999).

  80. 80.

    Collisson, E. A. et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

  81. 81.

    Hammerman, P. S. et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).

  82. 82.

    Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

  83. 83.

    Iglesia, M. D. et al. Genomic analysis of immune cell infiltrates across 11 tumor types. J. Natl Cancer Inst. 108, djw144 (2016).

  84. 84.

    Mount, D. W. et al. Using logistic regression to improve the prognostic value of microarray gene expression data sets: application to early-stage squamous cell carcinoma of the lung and triple negative breast carcinoma. BMC Med. Genom. 7, 33 (2014).

  85. 85.

    Torre, L. A., Siegel, R. L. & Jemal, A. Lung cancer statistics. Adv. Exp. Med. Biol. 893, 1–19 (2016).

  86. 86.

    Sorrentino, R. et al. B cells contribute to the anti-tumor activity of CpG-oligodeoxynucleotide in a mouse model of metastatic lung carcinoma. Am. J. Respir. Crit. Care. Med. 183, 1369–1379 (2011).

  87. 87.

    Li, Q., Teitz-Tennenbaum, S., Donald, E. J., Li, M. & Chang, A. E. In vivo sensitized and in vitro activated B cells mediate tumor regression in cancer adoptive immunotherapy. J. Immunol. 183, 3195–3203 (2009).

  88. 88.

    Tao, H. et al. Antitumor effector B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. Eur. J. Immunol. 45, 999–1009 (2015).

  89. 89.

    Bodogai, M. et al. Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L. Cancer Res. 73, 2127–2138 (2013).

  90. 90.

    Liao, S. F. et al. Immunization of fucose-containing polysaccharides from Reishi mushroom induces antibodies to tumor-associated Globo H-series epitopes. Proc. Natl Acad. Sci. USA 110, 13809–13814 (2013).

  91. 91.

    Chapoval, A. I., Fuller, J. A., Kremlev, S. G., Kamdar, S. J. & Evans, R. Combination chemotherapy and IL-15 administration induce permanent tumor regression in a mouse lung tumor model: NK and T cell-mediated effects antagonized by B cells. J. Immunol. 161, 6977–6984 (1998).

  92. 92.

    Kim, S. et al. B-cell depletion using an anti-CD20 antibody augments anti-tumor immune responses and immunotherapy in nonhematopoetic murine tumor models. J. Immunother. 31, 446–457 (2008).

  93. 93.

    Joly-Battaglini, A. et al. Rituximab efficiently depletes B cells in lung tumors and normal lung tissue. F1000Res. 5, 38 (2016).

  94. 94.

    Lee-Chang, C. et al. Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory B cells. J. Immunol. 191, 4141–4151 (2013).

  95. 95.

    Song, S. S. et al. Protective effects of total glucosides of paeony on N-nitrosodiethylamine-induced hepatocellular carcinoma in rats via down-regulation of regulatory B cells. Immunol. Invest. 44, 521–535 (2015).

  96. 96.

    Wang, Z. et al. Lipid mediator lipoxin A4 inhibits tumor growth by targeting IL-10-producing regulatory B (Breg) cells. Cancer Lett. 364, 118–124 (2015).

  97. 97.

    Wejksza, K. et al. Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B cells via peroxisome proliferator-activated receptor α. J. Immunol. 190, 2575–2584 (2013).

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant #81502202), the Canadian Cancer Society Research Institute (grant #704121), the China Postdoctoral Science Foundation (grant #2017M611329), and the Scientific Research Project in the Science and Technology Development Plan of Jilin Province (grant #20150520142JH).

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Affiliations

  1. Department of Translational Medicine, The First Hospital of Jilin University, Changchun, 130061, China

    • Si-si Wang
    • , Wei Liu
    •  & Hao Xu
  2. Department of Thoracic surgery, The First Hospital of Jilin University, Changchun, 130021, China

    • Wei Liu
  3. Toronto General Hospital Research Institute, University Health Network, Toronto, ON, M5G 1L7, Canada

    • Dalam Ly
    •  & Li Zhang
  4. Departments of Laboratory Medicine and Pathobiology, Immunology, University of Toronto, Toronto, ON, M5G 1L7, Canada

    • Dalam Ly
    •  & Li Zhang
  5. Department of Pathology, The First Hospital of Jilin University, Changchun, 130021, China

    • Limei Qu

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The authors declare no competing interests.

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Correspondence to Wei Liu or Li Zhang.

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