Skip to main content
SpringerLink
Log in

Targeting Immune Checkpoints in Lung Cancer: Current Landscape and Future Prospects

  • Review Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Lung cancer is the most prevalent and deadly cancer worldwide. Immune checkpoint therapy, which targets regulatory pathways in T cells to boost anti-tumor immune response, has revolutionized lung cancer treatment paradigms. Inhibitors of the most established immune checkpoints such as programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) have been approved by the US Food and Drug Administration in the management of lung cancer. Despite the pronounced survival benefits that have been seen with immune checkpoint inhibitors, not all lung cancer patients respond to single-agent immunotherapy due to the complexity of the immune microenvironment and tumor resistance. Alternative immune checkpoints beyond PD-1/PD-L1 must be sought so that more patients can benefit from immune checkpoint therapy. Additionally, novel combination strategies of immunotherapy and conventional treatments (e.g., chemotherapy, radiotherapy, and targeted therapy) have shown promise in some clinical trials. Meanwhile, identification of predictive biomarkers is pivotal in selecting eligible patients for immunotherapy and to guide individualized clinical decision-making. The future of immune checkpoint therapy in lung cancer is not devoid of challenges, and more prospective clinical studies are awaited to translate our understanding from bench to bedside.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. https://doi.org/10.3322/caac.21442.

    Article  PubMed  Google Scholar 

  2. Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet. 2013;382(9893):709–19. https://doi.org/10.1016/S0140-6736(13)61502-0.

    Article  CAS  PubMed  Google Scholar 

  3. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, et al. Non-small cell lung cancer, version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15(4):504–35.

    Article  Google Scholar 

  4. Zhao X, Subramanian S. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Res. 2017;77(4):817–22. https://doi.org/10.1158/0008-5472.CAN-16-2379.

    Article  CAS  PubMed  Google Scholar 

  5. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–51.

    Article  CAS  Google Scholar 

  6. Malhotra J, Jabbour SK, Aisner J. Current state of immunotherapy for non-small cell lung cancer. Transl Lung Cancer Res. 2017;6(2):196–211. https://doi.org/10.21037/tlcr.2017.03.01.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23. https://doi.org/10.1016/j.cell.2017.01.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35. https://doi.org/10.1056/NEJMoa1504627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. https://doi.org/10.1056/NEJMoa1507643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33. https://doi.org/10.1056/NEJMoa1606774.

    Article  CAS  PubMed  Google Scholar 

  11. Torphy RJ, Schulick RD, Zhu Y. Newly emerging immune checkpoints: promises for future cancer therapy. Int J Mol Sci. 2017. https://doi.org/10.3390/ijms18122642.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Attili I, Passaro A, Pavan A, Conte P, De Marinis F, Bonanno L. Combination immunotherapy strategies in advanced non-small cell lung cancer (NSCLC): does biological rationale meet clinical needs? Crit Rev Oncol Hematol. 2017;119:30–9. https://doi.org/10.1016/j.critrevonc.2017.09.007.

    Article  PubMed  Google Scholar 

  13. Ancevski Hunter K, Socinski MA, Villaruz LC. PD-L1 testing in guiding patient selection for PD-1/PD-L1 inhibitor therapy in lung cancer. Mol Diagn Ther. 2018;22(1):1–10. https://doi.org/10.1007/s40291-017-0308-6.

    Article  CAS  PubMed  Google Scholar 

  14. Ahmadzada T, Kao S, Reid G, Boyer M, Mahar A, Cooper WA. An update on predictive biomarkers for treatment selection in non-small cell lung cancer. J Clin Med. 2018;7(6):153. https://doi.org/10.3390/jcm7060153.

    Article  CAS  PubMed Central  Google Scholar 

  15. Honda T, Egen JG, Lammermann T, Kastenmuller W, Torabi-Parizi P, Germain RN. Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity. 2014;40(2):235–47. https://doi.org/10.1016/j.immuni.2013.11.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331.

    Article  CAS  PubMed  Google Scholar 

  17. Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415–26. https://doi.org/10.1056/NEJMoa1613493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378(22):2093–104. https://doi.org/10.1056/NEJMoa1801946.

    Article  CAS  PubMed  Google Scholar 

  19. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. https://doi.org/10.1056/NEJMoa1801005.

    Article  CAS  PubMed  Google Scholar 

  20. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–65. https://doi.org/10.1016/S0140-6736(16)32517-X.

    Article  PubMed  Google Scholar 

  21. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–301. https://doi.org/10.1056/NEJMoa1716948.

    Article  CAS  PubMed  Google Scholar 

  22. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, PACIFIC Investigators, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29. https://doi.org/10.1056/NEJMoa1709937.

    Article  CAS  PubMed  Google Scholar 

  23. Vokes EE, Ready N, Felip E, Horn L, Burgio MA, Antonia SJ, et al. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol. 2018;29(4):959–65. https://doi.org/10.1093/annonc/mdy041.

    Article  CAS  PubMed  Google Scholar 

  24. Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, et al. Molecular basis of T cell inactivation by CTLA-4. Science. 1998;282(5397):2263–6.

    Article  CAS  Google Scholar 

  25. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011;332(6029):600–3. https://doi.org/10.1126/science.1202947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/NEJMoa1003466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299–308. https://doi.org/10.1016/S1470-2045(15)00544-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171(5):1393–405.

    Article  CAS  Google Scholar 

  29. Workman CJ, Dugger KJ, Vignali DA. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol. 2002;169(10):5392–5.

    Article  CAS  Google Scholar 

  30. Durham NM, Nirschl CJ, Jackson CM, Elias J, Kochel CM, Anders RA, et al. Lymphocyte activation gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One. 2014;9(11):e109080. https://doi.org/10.1371/journal.pone.0109080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917–27. https://doi.org/10.1158/0008-5472.CAN-11-1620.

    Article  CAS  PubMed  Google Scholar 

  32. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci USA. 2010;107(17):7875–80. https://doi.org/10.1073/pnas.1003345107.

    Article  PubMed  Google Scholar 

  33. He Y, Yu H, Rozeboom L, Rivard CJ, Ellison K, Dziadziuszko R, et al. LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and Tumor-Infiltrating Lymphocytes. J Thorac Oncol. 2017;12(5):814–23. https://doi.org/10.1016/j.jtho.2017.01.019.

    Article  PubMed  Google Scholar 

  34. Wei T, Zhang J, Qin Y, Wu Y, Zhu L, Lu L, et al. Increased expression of immunosuppressive molecules on intratumoral and circulating regulatory T cells in non-small-cell lung cancer patients. Am J Cancer Res. 2015;5(7):2190–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117(11):3383–92. https://doi.org/10.1172/JCI31184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hahn AW, Gill DM, Pal SK, Agarwal N. The future of immune checkpoint cancer therapy after PD-1 and CTLA-4. Immunotherapy. 2017;9(8):681–92. https://doi.org/10.2217/imt-2017-0024.

    Article  CAS  PubMed  Google Scholar 

  37. Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O’Connell S, et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res. 2014;74(7):1924–32. https://doi.org/10.1158/0008-5472.CAN-13-1504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Flies DB, Han X, Higuchi T, Zheng L, Sun J, Ye JJ, et al. Coinhibitory receptor PD-1H preferentially suppresses CD4(+) T cell-mediated immunity. J Clin Invest. 2014;124(5):1966–75. https://doi.org/10.1172/JCI74589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Le Mercier I, Chen W, Lines JL, Day M, Li J, Sergent P, et al. VISTA regulates the development of protective antitumor immunity. Cancer Res. 2014;74(7):1933–44. https://doi.org/10.1158/0008-5472.CAN-13-1506.

    Article  CAS  PubMed  Google Scholar 

  40. Liu J, Yuan Y, Chen W, Putra J, Suriawinata AA, Schenk AD, et al. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci USA. 2015;112(21):6682–7. https://doi.org/10.1073/pnas.1420370112.

    Article  CAS  PubMed  Google Scholar 

  41. Gao J, Ward JF, Pettaway CA, Shi LZ, Subudhi SK, Vence LM, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017;23(5):551–5. https://doi.org/10.1038/nm.4308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Villarroel-Espindola F, Yu X, Datar I, Mani N, Sanmamed MF, Velcheti V, et al. Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer. Clin Cancer Res. 2018;24(7):1562–73. https://doi.org/10.1158/1078-0432.CCR-17-2542.

    Article  CAS  PubMed  Google Scholar 

  43. Zhao R, Chinai JM, Buhl S, Scandiuzzi L, Ray A, Jeon H, et al. HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc Natl Acad Sci USA. 2013;110(24):9879–84. https://doi.org/10.1073/pnas.1303524110.

    Article  PubMed  Google Scholar 

  44. Zhu Y, Yao S, Iliopoulou BP, Han X, Augustine MM, Xu H, et al. B7-H5 costimulates human T cells via CD28H. Nat Commun. 2013;4:2043. https://doi.org/10.1038/ncomms3043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Janakiram M, Chinai JM, Fineberg S, Fiser A, Montagna C, Medavarapu R, et al. Expression, clinical significance, and receptor identification of the newest B7 family member HHLA2 protein. Clin Cancer Res. 2015;21(10):2359–66. https://doi.org/10.1158/1078-0432.CCR-14-1495.

    Article  CAS  PubMed  Google Scholar 

  46. Cheng H, Janakiram M, Borczuk A, Lin J, Qiu W, Liu H, et al. HHLA2, a new immune checkpoint member of the B7 family, is widely expressed in human lung cancer and associated with EGFR mutational status. Clin Cancer Res. 2017;23(3):825–32. https://doi.org/10.1158/1078-0432.CCR-15-3071.

    Article  CAS  PubMed  Google Scholar 

  47. Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunol Rev. 2017;276(1):97–111. https://doi.org/10.1111/imr.12520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245–52. https://doi.org/10.1038/ni1271.

    Article  CAS  PubMed  Google Scholar 

  49. Rangachari M, Zhu C, Sakuishi K, Xiao S, Karman J, Chen A, et al. Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat Med. 2012;18(9):1394–400. https://doi.org/10.1038/nm.2871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8 + T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175–86. https://doi.org/10.1084/jem.20100637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gao X, Zhu Y, Li G, Huang H, Zhang G, Wang F, et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One. 2012;7(2):e30676. https://doi.org/10.1371/journal.pone.0030676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu L, Huang Y, Tan L, Yu W, Chen D, Lu C, et al. Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int Immunopharmacol. 2015;29(2):635–41. https://doi.org/10.1016/j.intimp.2015.09.017.

    Article  CAS  PubMed  Google Scholar 

  53. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501. https://doi.org/10.1038/ncomms10501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Levin SD, Taft DW, Brandt CS, Bucher C, Howard ED, Chadwick EM, et al. Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur J Immunol. 2011;41(4):902–15. https://doi.org/10.1002/eji.201041136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med. 2003;198(4):557–67. https://doi.org/10.1084/jem.20030788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, Levin SD, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol. 2011;186(3):1338–42. https://doi.org/10.4049/jimmunol.1003081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10(1):48–57. https://doi.org/10.1038/ni.1674.

    Article  CAS  PubMed  Google Scholar 

  58. Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, Novik A, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A. 2009;106(42):17858–63. https://doi.org/10.1073/pnas.0903474106.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923–37. https://doi.org/10.1016/j.ccell.2014.10.018.

    Article  CAS  PubMed  Google Scholar 

  60. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98–106. https://doi.org/10.1097/COC.0000000000000239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol. 2018;29(1):71–83. https://doi.org/10.1093/annonc/mdx686.

    Article  CAS  PubMed  Google Scholar 

  62. Illidge T. Turning radiotherapy into an effective systemic anti-cancer treatment in combination with immunotherapy. Clin Oncol (R Coll Radiol). 2015;27(12):696–9. https://doi.org/10.1016/j.clon.2015.09.001.

    Article  CAS  PubMed  Google Scholar 

  63. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–7. https://doi.org/10.1038/nature14292.

    Article  CAS  PubMed  Google Scholar 

  64. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1(6):365–72. https://doi.org/10.1158/2326-6066.CIR-13-0115.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18(7):895–903. https://doi.org/10.1016/S1470-2045(17)30380-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Takamori S, Toyokawa G, Takada K, Shoji F, Okamoto T, Maehara Y. Combination therapy of radiotherapy and anti-PD-1/PD-L1 treatment in non-small-cell lung cancer: a mini-review. Clin Lung Cancer. 2018;19(1):12–6. https://doi.org/10.1016/j.cllc.2017.06.015.

    Article  CAS  PubMed  Google Scholar 

  67. Zheng H, Zeltsman M, Zauderer MG, Eguchi T, Vaghjiani RG, Adusumilli PS. Chemotherapy-induced immunomodulation in non-small-cell lung cancer: a rationale for combination chemoimmunotherapy. Immunotherapy. 2017;9(11):913–27. https://doi.org/10.2217/imt-2017-0052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu WM, Fowler DW, Smith P, Dalgleish AG. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer. 2010;102(1):115–23. https://doi.org/10.1038/sj.bjc.6605465.

    Article  CAS  PubMed  Google Scholar 

  69. Zhang P, Ma Y, Lv C, Huang M, Li M, Dong B, et al. Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy. Cancer Sci. 2016;107(11):1563–71. https://doi.org/10.1111/cas.13072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Melero I, Berman DM, Aznar MA, Korman AJ, Perez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457–72. https://doi.org/10.1038/nrc3973.

    Article  CAS  PubMed  Google Scholar 

  71. Okita R, Yukawa T, Nojima Y, Maeda A, Saisho S, Shimizu K, et al. MHC class I chain-related molecule A and B expression is upregulated by cisplatin and associated with good prognosis in patients with non-small cell lung cancer. Cancer Immunol Immunother. 2016;65(5):499–509. https://doi.org/10.1007/s00262-016-1814-9.

    Article  CAS  PubMed  Google Scholar 

  72. Palma JP, Aggarwal SK. Cisplatin and carboplatin-mediated activation of murine peritoneal macrophages in vitro: production of interleukin-1 alpha and tumor necrosis factor-alpha. Anticancer Drugs. 1995;6(2):311–6.

    Article  CAS  Google Scholar 

  73. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040–51. https://doi.org/10.1056/NEJMoa1810865.

    Article  CAS  PubMed  Google Scholar 

  74. Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017. https://doi.org/10.1126/scitranslmed.aak9679.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA. 2012;109(43):17561–6. https://doi.org/10.1073/pnas.1215397109.

    Article  PubMed  Google Scholar 

  76. Gettinger S, Chow LQ, Borghaei H, Shen Y, Harbison C, Chen AC, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced non-small cell lung cancer (NSCLC): metastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014;90(5, Supplement):S34–5. https://doi.org/10.1016/j.ijrobp.2014.08.210.

    Article  Google Scholar 

  77. Ahn MJ, Yang J, Yu H, Saka H, Ramalingam S, Goto K, et al. 136O: Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial [abstract no. 136O]. J Thorac Oncol. 2016;11(4 Suppl):S115. https://doi.org/10.1016/S1556-0864(16)30246-5.

    Article  Google Scholar 

  78. Santini FC, Hellmann MD. PD-1/PD-L1 axis in lung cancer. Cancer J. 2018;24(1):15–9. https://doi.org/10.1097/PPO.0000000000000300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Thunnissen E, de Langen AJ, Smit EF. PD-L1 IHC in NSCLC with a global and methodological perspective. Lung Cancer. 2017;113:102–5. https://doi.org/10.1016/j.lungcan.2017.09.010.

    Article  PubMed  Google Scholar 

  80. Ilie M, Szafer-Glusman E, Hofman V, Chamorey E, Lalvee S, Selva E, et al. Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small-cell lung cancer. Ann Oncol. 2018;29(1):193–9. https://doi.org/10.1093/annonc/mdx636.

    Article  CAS  PubMed  Google Scholar 

  81. Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol. 2018;36(7):633–41. https://doi.org/10.1200/JCO.2017.75.3384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9. https://doi.org/10.1126/science.aaf1490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Boyiadzis MM, Kirkwood JM, Marshall JL, Pritchard CC, Azad NS, Gulley JL. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer. 2018;6(1):35. https://doi.org/10.1186/s40425-018-0342-x.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Mazzaschi G, Madeddu D, Falco A, Bocchialini G, Goldoni M, Sogni F, et al. Low PD-1 Expression in cytotoxic CD8(+) tumor-infiltrating lymphocytes confers an immune-privileged tissue microenvironment in NSCLC with a prognostic and predictive value. Clin Cancer Res. 2018;24(2):407–19. https://doi.org/10.1158/1078-0432.CCR-17-2156.

    Article  CAS  PubMed  Google Scholar 

  85. Kamphorst AO, Pillai RN, Yang S, Nasti TH, Akondy RS, Wieland A, et al. Proliferation of PD-1 + CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci USA. 2017;114(19):4993–8. https://doi.org/10.1073/pnas.1705327114.

    Article  CAS  PubMed  Google Scholar 

  86. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785–92. https://doi.org/10.1200/JCO.2015.66.1389.

    Article  CAS  PubMed  Google Scholar 

  87. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68. https://doi.org/10.1056/NEJMra1703481.

    Article  CAS  PubMed  Google Scholar 

  88. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242–50. https://doi.org/10.1158/1078-0432.CCR-16-3133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, School of Basic Medical Science, Wuhan University, 185 Donghu Road, Medical Building 8, 10th Floor, Wuchang District, Wuhan, 430071, Hubei, People’s Republic of China

    Long Long, Muqimova Ozarina, Xianda Zhao & Honglei Chen

  2. Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China

    Long Long

  3. Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China

    Chen Zhao

  4. Department of Pharmacology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, People’s Republic of China

    Jing Yang

  5. Hubei Province Key Laboratory of Allergy and Immune-related Diseases, Wuhan University, Wuhan, 430071, People’s Republic of China

    Honglei Chen

Authors
  1. Long Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chen Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muqimova Ozarina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xianda Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Honglei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Honglei Chen.

Ethics declarations

Conflict of Interests

Long Long, Chen Zhao, Muqimova Ozarina, Xianda Zhao, Jing Yang, and Honglei Chen have no conflicts of interest related to this article.

Funding

This work was supported by grants from the National Undergraduate Innovation Project of China (Nos. 201710486100; 201810486098) and Public Welfare Technology Application Research of Zhejiang Province (No. 2016C33236).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Long, L., Zhao, C., Ozarina, M. et al. Targeting Immune Checkpoints in Lung Cancer: Current Landscape and Future Prospects. Clin Drug Investig 39, 341–353 (2019). https://doi.org/10.1007/s40261-018-00746-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-018-00746-5

Search

Navigation