Advertisement

Targeting the Lung Cancer Microenvironment: Harnessing Host Responses

  • Mark M. Fuster
Chapter

Abstract

Understanding the host response to lung cancer is critical in the development of long-term therapeutic responses and cures for advanced-stage disease. While state-of-the-art treatments that target the tumor cell directly are effective as initial antitumor approaches, strategies that augment antitumor host responses are highly appealing, and may overcome resistance through novel discoveries. These involve (1) discovery of basic mechanisms by which the tumor “hijacks” host immune regulation and vascular homeostasis (thus promoting tumor growth), and (2) discovery of tumor-resistance pathways that counter immune- and/or vascular-targeting therapies. Major mechanisms by which lung carcinoma is able to usurp host mechanisms include both the tumor’s manipulation of immune checkpoint regulatory pathways (with a cytokine and dendritic cell balance that maintains a high suppressor/effector T-cell ratio) and the remodeling of blood and lymphatic vasculature by multiple endothelial mitogens, thereby promoting tumor growth and dissemination. Lymphatic dissemination in particular involves not only tumor cells but also immunosuppressive dendritic cell trafficking to tumor-draining lymph nodes. Novel approaches to overcome these challenges include immune checkpoint-blocking strategies (e.g., PD-1/PD-L1 or CTLA4 blockade which inhibit T-effector suppression) or agonists to T-stimulatory pathways, such as OX40 or 4-1BB. They also include vaccine development and/or approaches to manipulate dendritic cells or engineer T cells (e.g., CAR-T cells) against antigens that are (preferably) clonally expressed by the entire tumor. Major limitations to these approaches include poor tumor-antigen recognition or presentation by dendritic cells or hyporesponsive T cells in the immunosuppressive tumor microenvironment. Moreover, autoimmune-type side effects of immune checkpoint T-cell targeting or T-cell engineering present therapeutic challenges. Finally, the discovery of tumor neo-antigens, which are known to be more abundantly expressed in tumors initiated by environmental stimuli (e.g., melanoma or squamous lung carcinoma), as well as their ability to predict T cell responsiveness, is another important development in the quest to augment host immune responses to lung cancer. These discoveries will be valuable in promoting a set of strategies that markedly improve the chances for durable remissions or cures in the setting of advanced-stage lung cancer or even recurrent disease following definitive treatments.

Keywords

Lung cancer Immunity Lymphatic Neo-antigen Host 

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30CrossRefPubMedGoogle Scholar
  2. 2.
    Detterbeck FC, Postmus PE, Tanoue LT (2013) The stage classification of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of chest physicians evidence-based clinical practice guidelines. Chest 143(5 Suppl):e191S–e210SCrossRefPubMedGoogle Scholar
  3. 3.
    National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD et al (2011) Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365(5):395–409CrossRefGoogle Scholar
  4. 4.
    Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hall RD, Le TM, Haggstrom DE, Gentzler RD (2015) Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl Lung Cancer Res 4(5):515–523PubMedPubMedCentralGoogle Scholar
  6. 6.
    Yuan A, Hsiao YJ, Chen HY, Chen HW, Ho CC, Chen YY et al (2015) Opposite effects of M1 and M2 macrophage subtypes on lung cancer progression. Sci Rep 5:14273CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Das M, Wakelee H (2014) Angiogenesis and lung cancer: ramucirumab prolongs survival in 2(nd)-line metastatic NSCLC. Transl Lung Cancer Res 3(6):397–399PubMedPubMedCentralGoogle Scholar
  8. 8.
    Reck M, Mellemgaard A (2015) Emerging treatments and combinations in the management of NSCLC: clinical potential of nintedanib. Biologics 9:47–56PubMedPubMedCentralGoogle Scholar
  9. 9.
    Chu BF, GA O (2016) Incorporation of antiangiogenic therapy into the non-small-cell lung cancer paradigm. Clin Lung Cancer 17:493–506CrossRefPubMedGoogle Scholar
  10. 10.
    Chang YW, Su CM, Su YH, Ho YS, Lai HH, Chen HA et al (2014) Novel peptides suppress VEGFR-3 activity and antagonize VEGFR-3-mediated oncogenic effects. Oncotarget 5(11):3823–3835CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Couraud S, Zalcman G, Milleron B, Morin F, Souquet PJ (2012) Lung cancer in never smokers–a review. Eur J Cancer 48(9):1299–1311CrossRefPubMedGoogle Scholar
  12. 12.
    Skrzypski M, Czapiewski P, Goryca K, Jassem E, Wyrwicz L, Pawlowski R et al (2014) Prognostic value of microRNA expression in operable non-small cell lung cancer patients. Br J Cancer 110(4):991–1000CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361(10):947–957CrossRefPubMedGoogle Scholar
  14. 14.
    Sellmann L, Fenchel K, Dempke WC (2015) Improved overall survival following tyrosine kinase inhibitor treatment in advanced or metastatic non-small-cell lung cancer-the Holy Grail in cancer treatment? Transl Lung Cancer Res 4(3):223–227PubMedPubMedCentralGoogle Scholar
  15. 15.
    Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10CrossRefPubMedGoogle Scholar
  16. 16.
    Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S et al (2014) Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol 11(9):509–524CrossRefPubMedGoogle Scholar
  17. 17.
    Zamarron BF, Chen W (2011) Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 7(5):651–658CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Thomas A, Giaccone G (2015) Why has active immunotherapy not worked in lung cancer? Ann Oncol 26(11):2213–2220CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Schneider T, Hoffmann H, Dienemann H, Schnabel PA, Enk AH, Ring S et al (2011) Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7-H3. J Thorac Oncol 6(7):1162–1168CrossRefPubMedGoogle Scholar
  20. 20.
    Finn OJ (2008) Cancer immunology. N Engl J Med 358(25):2704–2715CrossRefPubMedGoogle Scholar
  21. 21.
    Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer immunoediting and its three component phases–elimination, equilibrium and escape. Curr Opin Immunol 27:16–25CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Anagnostou VK, Brahmer JR (2015) Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res 21(5):976–984CrossRefPubMedGoogle Scholar
  24. 24.
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028CrossRefPubMedGoogle Scholar
  25. 25.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387(10027):1540–1550CrossRefPubMedGoogle Scholar
  27. 27.
    Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J et al (2016) Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387(10030):1837–1846CrossRefPubMedGoogle Scholar
  28. 28.
    Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ et al (2015) Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol 16(3):257–265CrossRefPubMedGoogle Scholar
  29. 29.
    Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Leone RD, Lo YC, Powell JD (2015) A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J 13:265–272CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Farkona S, Diamandis EP, Blasutig IM (2016) Cancer immunotherapy: the beginning of the end of cancer? BMC Med 14:73CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161(2):205–214CrossRefPubMedGoogle Scholar
  33. 33.
    Rooney C, Sethi T (2015) Advances in molecular biology of lung disease: aiming for precision therapy in non-small cell lung cancer. Chest 148(4):1063–1072CrossRefPubMedGoogle Scholar
  34. 34.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al (2013) Signatures of mutational processes in human cancer. Nature 500(7463):415–421CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK et al (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351(6280):1463–1469CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M et al (2014) Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 15(1):59–68CrossRefPubMedGoogle Scholar
  40. 40.
    Gubin MM, Artyomov MN, Mardis ER, Schreiber RD (2015) Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest 125(9):3413–3421CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Arriola E, Ottensmeier C (2016) TG4010: a vaccine with a therapeutic role in cancer. Immunotherapy 8(5):511–519CrossRefPubMedGoogle Scholar
  42. 42.
    Alfonso S, Valdes-Zayas A, Santiesteban ER, Flores YI, Areces F, Hernandez M et al (2014) A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res 20(14):3660–3671CrossRefPubMedGoogle Scholar
  43. 43.
    Deloch L, Derer A, Hartmann J, Frey B, Fietkau R, Gaipl US (2016) Modern radiotherapy concepts and the impact of radiation on immune activation. Front Oncol 6:141CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Giaccone G, Bazhenova LA, Nemunaitis J, Tan M, Juhasz E, Ramlau R et al (2015) A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 51(16):2321–2329CrossRefPubMedGoogle Scholar
  45. 45.
    Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR et al (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124(2):687–695CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Sharabi AB, Nirschl CJ, Kochel CM, Nirschl TR, Francica BJ, Velarde E et al (2015) Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res 3(4):345–355CrossRefPubMedGoogle Scholar
  47. 47.
    Hinrichs CS, Rosenberg SA (2014) Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev 257(1):56–71CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Yee C (2013) Adoptive T-cell therapy for cancer: boutique therapy or treatment modality? Clin Cancer Res 19(17):4550–4552CrossRefPubMedGoogle Scholar
  49. 49.
    Morgan RA, Dudley ME, Rosenberg SA (2010) Adoptive cell therapy: genetic modification to redirect effector cell specificity. Cancer J 16(4):336–341CrossRefPubMedGoogle Scholar
  50. 50.
    Gross G, Waks T, Eshhar Z (1989) Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 86(24):10024–10028CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA et al (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385(9967):517–528CrossRefPubMedGoogle Scholar
  52. 52.
    Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148CrossRefPubMedGoogle Scholar
  53. 53.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422CrossRefPubMedGoogle Scholar
  54. 54.
    Lesterhuis WJ, Haanen JB, Punt CJ (2011) Cancer immunotherapy–revisited. Nat Rev Drug Discov 10(8):591–600CrossRefPubMedGoogle Scholar
  55. 55.
    El Ghazal R, Yin X, Johns SC, Swanson L, Macal M, Ghosh P et al (2016) Glycan sulfation modulates dendritic cell biology and tumor growth. Neoplasia 18(5):294–306CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140(4):460–476CrossRefPubMedGoogle Scholar
  57. 57.
    Felts RL, Narayan K, Estes JD, Shi D, Trubey CM, Fu J et al (2010) 3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells. Proc Natl Acad Sci U S A 107(30):13336–13341CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Singapore 2017

Authors and Affiliations

  1. 1.Division of Pulmonary & Critical Care, Department of Medicine, VA San Diego Healthcare SystemUniversity of California, San DiegoSan DiegoUSA

Personalised recommendations