Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non–small cell lung cancer

Lung Cancer

Volumn 99, Issue , 2016, Pages 79-87

  Shien, Kazuhiko ^a   Papadimitrakopoulou, Vassiliki A ^a   Wistuba, Ignacio I ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

Author keywords

Biomarker; Immune checkpoint inhibition; NSCLC; PD 1; PD L1

Indexed keywords

BIOLOGICAL MARKER; PD L2 PROTEIN; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN; PROTEIN INHIBITOR; UNCLASSIFIED DRUG; CD274 PROTEIN, HUMAN; IMMUNOLOGICAL ANTINEOPLASTIC AGENT; PROGRAMMED DEATH 1 LIGAND 1; TUMOR MARKER;

BONE MARROW CELL; CD8+ T LYMPHOCYTE; CLINICAL FEATURE; CLINICAL TRIAL (TOPIC); DEMOGRAPHY; EFFECTOR CELL; EPITHELIAL MESENCHYMAL TRANSITION; GENE EXPRESSION; GENE MUTATION; HISTOPATHOLOGY; HUMAN; IMMUNOCOMPETENT CELL; MUTATION; MUTATIONAL LOAD; NON SMALL CELL LUNG CANCER; ONCOGENE; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; REVIEW; SMOKING; SUPPRESSOR CELL; TUMOR CELL; TUMOR MICROENVIRONMENT; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; GENETICS; IMMUNOLOGY; IMMUNOMODULATION; LUNG TUMOR; METABOLISM; MOLECULARLY TARGETED THERAPY; MORTALITY; PROGNOSIS; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

ANTINEOPLASTIC AGENTS, IMMUNOLOGICAL; B7-H1 ANTIGEN; BIOMARKERS, TUMOR; CARCINOMA, NON-SMALL-CELL LUNG; EPITHELIAL-MESENCHYMAL TRANSITION; GENE EXPRESSION; HUMANS; IMMUNOMODULATION; LUNG NEOPLASMS; MOLECULAR TARGETED THERAPY; MUTATION; PROGNOSIS; PROGRAMMED CELL DEATH 1 RECEPTOR; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; TUMOR MICROENVIRONMENT;

EID: 84977274739     PISSN: 01695002     EISSN: 18728332     Source Type: Journal    
DOI: 10.1016/j.lungcan.2016.06.016     Document Type: Review

References (77)

1. [1] Schiller, J.H., Harrington, D., Belani, C.P., Langer, C., Sandler, A., Krook, J., Zhu, J., Johnson, D.H., Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N. Engl. J. Med. 346 (2002), 92–98.
2. [2] Ohe, Y., Ohashi, Y., Kubota, K., Tamura, T., Nakagawa, K., Negoro, S., Nishiwaki, Y., Saijo, N., Ariyoshi, Y., Fukuoka, M., Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann. Oncol. 18 (2007), 317–323.
3. [3] Gentzler, R.D., Johnson, M.L., Complex decisions for first-line and maintenance treatment of advanced wild-type non-small cell lung cancer. Oncologist 20 (2015), 299–306.
4. [4] Pao, W., Girard, N., New driver mutations in non-small-cell lung cancer. Lancet Oncol. 12 (2011), 175–180.
5. [5] Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., Fujita, Y., Okinaga, S., Hirano, H., Yoshimori, K., Harada, T., Ogura, T., Ando, M., Miyazawa, H., Tanaka, T., Saijo, Y., Hagiwara, K., Morita, S., Nukiwa, T., Group N-EJS. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362 (2010), 2380–2388.
6. [6] Jackman, D., Pao, W., Riely, G.J., Engelman, J.A., Kris, M.G., Janne, P.A., Lynch, T., Johnson, B.E., Miller, V.A., Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J. Clin. Oncol. 28 (2010), 357–360.
7. [7] Brahmer, J.R., Drake, C.G., Wollner, I., Powderly, J.D., Picus, J., Sharfman, W.H., Stankevich, E., Pons, A., Salay, T.M., McMiller, T.L., Gilson, M.M., Wang, C., Selby, M., Taube, J.M., Anders, R., Chen, L., Korman, A.J., Pardoll, D.M., Lowy, I., Topalian, S.L., Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28 (2010), 3167–3175.
8. [8] Brahmer, J.R., Tykodi, S.S., Chow, L.Q., Hwu, W.J., Topalian, S.L., Hwu, P., Drake, C.G., Camacho, L.H., Kauh, J., Odunsi, K., Pitot, H.C., Hamid, O., Bhatia, S., Martins, R., Eaton, K., Chen, S., Salay, T.M., Alaparthy, S., Grosso, J.F., Korman, A.J., Parker, S.M., Agrawal, S., Goldberg, S.M., Pardoll, D.M., Gupta, A., Wigginton, J.M., Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366 (2012), 2455–2465.
9. [9] Topalian, S.L., Hodi, F.S., Brahmer, J.R., Gettinger, S.N., Smith, D.C., McDermott, D.F., Powderly, J.D., Carvajal, R.D., Sosman, J.A., Atkins, M.B., Leming, P.D., Spigel, D.R., Antonia, S.J., Horn, L., Drake, C.G., Pardoll, D.M., Chen, L., Sharfman, W.H., Anders, R.A., Taube, J.M., McMiller, T.L., Xu, H., Korman, A.J., Jure-Kunkel, M., Agrawal, S., McDonald, D., Kollia, G.D., Gupta, A., Wigginton, J.M., Sznol, M., Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366 (2012), 2443–2454.
10. [10] Herbst, R.S., Soria, J.C., Kowanetz, M., Fine, G.D., Hamid, O., Gordon, M.S., Sosman, J.A., McDermott, D.F., Powderly, J.D., Gettinger, S.N., Kohrt, H.E., Horn, L., Lawrence, D.P., Rost, S., Leabman, M., Xiao, Y., Mokatrin, A., Koeppen, H., Hegde, P.S., Mellman, I., Chen, D.S., Hodi, F.S., Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515 (2014), 563–567.
11. [11] Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D.R., Steins, M., Ready, N.E., Chow, L.Q., Vokes, E.E., Felip, E., Holgado, E., Barlesi, F., Kohlhaufl, M., Arrieta, O., Burgio, M.A., Fayette, J., Lena, H., Poddubskaya, E., Gerber, D.E., Gettinger, S.N., Rudin, C.M., Rizvi, N., Crino, L., Blumenschein, G.R. Jr., Antonia, S.J., Dorange, C., Harbison, C.T., Graf Finckenstein, F., Brahmer, J.R., Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373 (2015), 1627–1639.
12. [12] Brahmer, J., Reckamp, K.L., Baas, P., Crino, L., Eberhardt, W.E., Poddubskaya, E., Antonia, S., Pluzanski, A., Vokes, E.E., Holgado, E., Waterhouse, D., Ready, N., Gainor, J., Aren Frontera, O., Havel, L., Steins, M., Garassino, M.C., Aerts, J.G., Domine, M., Paz-Ares, L., Reck, M., Baudelet, C., Harbison, C.T., Lestini, B., Spigel, D.R., Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373 (2015), 123–135.
13. [13] Garon, E.B., Rizvi, N.A., Hui, R., Leighl, N., Balmanoukian, A.S., Eder, J.P., Patnaik, A., Aggarwal, C., Gubens, M., Horn, L., Carcereny, E., Ahn, M.J., Felip, E., Lee, J.S., Hellmann, M.D., Hamid, O., Goldman, J.W., Soria, J.C., Dolled-Filhart, M., Rutledge, R.Z., Zhang, J., Lunceford, J.K., Rangwala, R., Lubiniecki, G.M., Roach, C., Emancipator, K., Gandhi, L., Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med., 2015.
14. [14] Gettinger, S.N., Horn, L., Gandhi, L., Spigel, D.R., Antonia, S.J., Rizvi, N.A., Powderly, J.D., Heist, R.S., Carvajal, R.D., Jackman, D.M., Sequist, L.V., Smith, D.C., Leming, P., Carbone, D.P., Pinder-Schenck, M.C., Topalian, S.L., Hodi, F.S., Sosman, J.A., Sznol, M., McDermott, D.F., Pardoll, D.M., Sankar, V., Ahlers, C.M., Salvati, M., Wigginton, J.M., Hellmann, M.D., Kollia, G.D., Gupta, A.K., Brahmer, J.R., Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J. Clin. Oncol. 33 (2015), 2004–2012.
15. [15] Rizvi, N.A., Mazieres, J., Planchard, D., Stinchcombe, T.E., Dy, G.K., Antonia, S.J., Horn, L., Lena, H., Minenza, E., Mennecier, B., Otterson, G.A., Campos, L.T., Gandara, D.R., Levy, B.P., Nair, S.G., Zalcman, G., Wolf, J., Souquet, P.J., Baldini, E., Cappuzzo, F., Chouaid, C., Dowlati, A., Sanborn, R., Lopez-Chavez, A., Grohe, C., Huber, R.M., Harbison, C.T., Baudelet, C., Lestini, B.J., Ramalingam, S.S., 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 (2015), 257–265.
16. [16] Herbst, R.S., Baas, P., Kim, D.W., Felip, E., Perez-Gracia, J.L., Han, J.Y., Molina, J., Kim, J.H., Arvis, C.D., Ahn, M.J., Majem, M., Fidler, M.J., de Castro, G. Jr., Garrido, M., Lubiniecki, G.M., Shentu, Y., Im, E., Dolled-Filhart, M., Garon, E.B., Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2015.
17. [17] Barber, D.L., Wherry, E.J., Masopust, D., Zhu, B., Allison, J.P., Sharpe, A.H., Freeman, G.J., Ahmed, R., Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439 (2006), 682–687.
18. [18] Sharpe, A.H., Wherry, E.J., Ahmed, R., Freeman, G.J., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8 (2007), 239–245.
19. [19] Robert, C., Long, G.V., Brady, B., Dutriaux, C., Maio, M., Mortier, L., Hassel, J.C., Rutkowski, P., McNeil, C., Kalinka-Warzocha, E., Savage, K.J., Hernberg, M.M., Lebbe, C., Charles, J., Mihalcioiu, C., Chiarion-Sileni, V., Mauch, C., Cognetti, F., Arance, A., Schmidt, H., Schadendorf, D., Gogas, H., Lundgren-Eriksson, L., Horak, C., Sharkey, B., Waxman, I.M., Atkinson, V., Ascierto, P.A., Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372 (2015), 320–330.
20. [20] Zhang, Y., Huang, S., Gong, D., Qin, Y., Shen, Q., Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol. Immunol. 7 (2010), 389–395.
21. [21] Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12 (2012), 252–264.
22. [22] Blank, C., Gajewski, T.F., Mackensen, A., Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol. Immunother. 54 (2005), 307–314.
23. [23] Wang, A., Wang, H.Y., Liu, Y., Zhao, M.C., Zhang, H.J., Lu, Z.Y., Fang, Y.C., Chen, X.F., Liu, G.T., The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis. Eur. J. Surg. Oncol. 41 (2015), 450–456.
24. [24] Yang, C.Y., Lin, M.W., Chang, Y.L., Wu, C.T., Yang, P.C., Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. Eur. J. Cancer 50 (2014), 1361–1369.
25. [25] Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer–preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol 2010;37: 430–439.
26. [26] Weber, J.S., Kudchadkar, R.R., Yu, B., Gallenstein, D., Horak, C.E., Inzunza, H.D., Zhao, X., Martinez, A.J., Wang, W., Gibney, G., Kroeger, J., Eysmans, C., Sarnaik, A.A., Safety, Chen Y.A., efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or −naive melanoma. J. Clin. Oncol. 31 (2013), 4311–4318.
27. [27] Wolchok, J.D., Kluger, H., Callahan, M.K., Postow, M.A., Rizvi, N.A., Lesokhin, A.M., Segal, N.H., Ariyan, C.E., Gordon, R.A., Reed, K., Burke, M.M., Caldwell, A., Kronenberg, S.A., Agunwamba, B.U., Zhang, X., Lowy, I., Inzunza, H.D., Feely, W., Horak, C.E., Hong, Q., Korman, A.J., Wigginton, J.M., Gupta, A., Sznol, M., Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369 (2013), 122–133.
28. [28] Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.J., Cowey, C.L., Lao, C.D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., Ferrucci, P.F., Hill, A., Wagstaff, J., Carlino, M.S., Haanen, J.B., Maio, M., Marquez-Rodas, I., McArthur, G.A., Ascierto, P.A., Long, G.V., Callahan, M.K., Postow, M.A., Grossmann, K., Sznol, M., Dreno, B., Bastholt, L., Yang, A., Rollin, L.M., Horak, C., Hodi, F.S., Wolchok, J.D., Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373 (2015), 23–34.
29. [29] Postow, M.A., Chesney, J., Pavlick, A.C., Robert, C., Grossmann, K., McDermott, D., Linette, G.P., Meyer, N., Giguere, J.K., Agarwala, S.S., Shaheen, M., Ernstoff, M.S., Minor, D., Salama, A.K., Taylor, M., Ott, P.A., Rollin, L.M., Horak, C., Gagnier, P., Wolchok, J.D., Hodi, F.S., Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372 (2015), 2006–2017.
30. [30] Weber, J.S., D'Angelo, S.P., Minor, D., Hodi, F.S., Gutzmer, R., Neyns, B., Hoeller, C., Khushalani, N.I., Miller, W.H. Jr., Lao, C.D., Linette, G.P., Thomas, L., Lorigan, P., Grossmann, K.F., Hassel, J.C., Maio, M., Sznol, M., Ascierto, P.A., Mohr, P., Chmielowski, B., Bryce, A., Svane, I.M., Grob, J.J., Krackhardt, A.M., Horak, C., Lambert, A., Yang, A.S., Larkin, J., Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16 (2015), 375–384.
31. [31] Chaft JE, Chao B, Akerley WL, Gordon M, Antonia SJ, Callahan J, Sandler A, Funke R, Li Z, Fredrickson J, Kowanetz M, Gettinger SN. Evaluation of PD-L1 Expression in Metachronous Tumor Samples and FDG-PET as a Predictive Biomarker in Ph2 Study (FIR) of Atezolizumab (MPDL3280A). In presented at 16th World Conference on Lung Cancer; 6 September-9 September 2015; Oral 02.06. Denver, USA.
32. [32] Taube, J.M., Anders, R.A., Young, G.D., Xu, H., Sharma, R., McMiller, T.L., Chen, S., Klein, A.P., Pardoll, D.M., Topalian, S.L., Chen, L., Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med., 4, 2012 (127ra137).
33. [33] Taube, J.M., Klein, A., Brahmer, J.R., Xu, H., Pan, X., Kim, J.H., Chen, L., Pardoll, D.M., Topalian, S.L., Anders, R.A., Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20 (2014), 5064–5074.
34. [34] Sunshine, J., Taube, J.M., PD-1/PD-L1 inhibitors. Curr. Opin. Pharmacol. 23 (2015), 32–38.
35. [35] Fridman, W.H., Pages, F., Sautes-Fridman, C., Galon, J., The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12 (2012), 298–306.
36. [36] Barry, M., Bleackley, R.C., Cytotoxic T lymphocytes: all roads lead to death. Nat. Rev. Immunol. 2 (2002), 401–409.
37. [37] Hiraoka, K., Miyamoto, M., Cho, Y., Suzuoki, M., Oshikiri, T., Nakakubo, Y., Itoh, T., Ohbuchi, T., Kondo, S., Katoh, H., Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br. J. Cancer 94 (2006), 275–280.
38. [38] Al-Shibli, K.I., Donnem, T., Al-Saad, S., Persson, M., Bremnes, R.M., Busund, L.T., Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin. Cancer Res. 14 (2008), 5220–5227.
39. [39] Schalper, K.A., Brown, J., Carvajal-Hausdorf, D., McLaughlin, J., Velcheti, V., Syrigos, K.N., Herbst, R.S., Rimm, D.L., Objective measurement and clinical significance of TILs in non-small cell lung cancer. J. Natl. Cancer Inst., 2015, 107.
40. [40] Donnem, T., Hald, S.M., Paulsen, E.E., Richardsen, E., Al-Saad, S., Kilvaer, T.K., Brustugun, O.T., Helland, A., Lund-Iversen, M., Poehl, M., Olsen, K.E., Ditzel, H.J., Hansen, O., Al-Shibli, K., Kiselev, Y., Sandanger, T.M., Andersen, S., Pezzella, F., Bremnes, R.M., Busund, L.T., Stromal CD8+ T-cell density—a promising supplement to TNM staging in non-small cell lung cancer. Clin. Cancer Res. 21 (2015), 2635–2643.
41. [41] Hu-Lieskovan S, Goldman JW, Han M, Zaretsky J, Shintaku I, Wolf B, Abarca P, Walser T, Lisberg A, Slamon DJ, Dubinett SM, Ribas A, Garon EB. High Intratumoral T Cell Infiltration Correlated with Mutational Load and Response to Pembrolizumab in Non-Small Cell Lung Cancer. In presented at 16th World Conference on Lung Cancer; 6 September-9 September 2015; Oral 31.05. Denver, USA. 2015.
42. [42] Champiat, S., Ferte, C., Lebel-Binay, S., Eggermont, A., Soria, J.C., Exomics and immunogenics: bridging mutational load and immune checkpoints efficacy. Oncoimmunology, 3, 2014, e27817.
43. [43] Rizvi, N.A., Hellmann, M.D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J.J., Lee, W., Yuan, J., Wong, P., Ho, T.S., Miller, M.L., Rekhtman, N., Moreira, A.L., Ibrahim, F., Bruggeman, C., Gasmi, B., Zappasodi, R., Maeda, Y., Sander, C., Garon, E.B., Merghoub, T., Wolchok, J.D., Schumacher, T.N., Chan, T.A., Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348 (2015), 124–128.
44. [44] Le, D.T., Uram, J.N., Wang, H., Bartlett, B.R., Kemberling, H., Eyring, A.D., Skora, A.D., Luber, B.S., Azad, N.S., Laheru, D., Biedrzycki, B., Donehower, R.C., Zaheer, A., Fisher, G.A., Crocenzi, T.S., Lee, J.J., Duffy, S.M., Goldberg, R.M., de la Chapelle, A., Koshiji, M., Bhaijee, F., Huebner, T., Hruban, R.H., Wood, L.D., Cuka, N., Pardoll, D.M., Papadopoulos, N., Kinzler, K.W., Zhou, S., Cornish, T.C., Taube, J.M., Anders, R.A., Eshleman, J.R., Vogelstein, B., Diaz, L.A. Jr., PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372 (2015), 2509–2520.
45. [45] Llosa, N.J., Cruise, M., Tam, A., Wicks, E.C., Hechenbleikner, E.M., Taube, J.M., Blosser, R.L., Fan, H., Wang, H., Luber, B.S., Zhang, M., Papadopoulos, N., Kinzler, K.W., Vogelstein, B., Sears, C.L., Anders, R.A., Pardoll, D.M., Housseau, F., The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5 (2015), 43–51.
46. [46] McGranahan, N., Furness, A.J., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S.K., Jamal-Hanjani, M., Wilson, G.A., Birkbak, N.J., Hiley, C.T., Watkins, T.B., Shafi, S., Murugaesu, N., Mitter, R., Akarca, A.U., Linares, J., Marafioti, T., Henry, J.Y., Van Allen, E.M., Miao, D., Schilling, B., Schadendorf, D., Garraway, L.A., Makarov, V., Rizvi, N.A., Snyder, A., Hellmann, M.D., Merghoub, T., Wolchok, J.D., Shukla, S.A., Wu, C.J., Peggs, K.S., Chan, T.A., Hadrup, S.R., Quezada, S.A., Swanton, C., Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science, 2016.
47. [47] Akbay, E.A., Koyama, S., Carretero, J., Altabef, A., Tchaicha, J.H., Christensen, C.L., Mikse, O.R., Cherniack, A.D., Beauchamp, E.M., Pugh, T.J., Wilkerson, M.D., Fecci, P.E., Butaney, M., Reibel, J.B., Soucheray, M., Cohoon, T.J., Janne, P.A., Meyerson, M., Hayes, D.N., Shapiro, G.I., Shimamura, T., Sholl, L.M., Rodig, S.J., Freeman, G.J., Hammerman, P.S., Dranoff, G., Wong, K.K., Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 3 (2013), 1355–1363.
48. [48] Azuma, K., Ota, K., Kawahara, A., Hattori, S., Iwama, E., Harada, T., Matsumoto, K., Takayama, K., Takamori, S., Kage, M., Hoshino, T., Nakanishi, Y., Okamoto, I., Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann. Oncol. 25 (2014), 1935–1940.
49. [49] Ota, K., Azuma, K., Kawahara, A., Hattori, S., Iwama, E., Tanizaki, J., Harada, T., Matsumoto, K., Takayama, K., Takamori, S., Kage, M., Hoshino, T., Nakanishi, Y., Okamoto, I., Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin. Cancer Res. 21 (2015), 4014–4021.
50. [50] Parsa, A.T., Waldron, J.S., Panner, A., Crane, C.A., Parney, I.F., Barry, J.J., Cachola, K.E., Murray, J.C., Tihan, T., Jensen, M.C., Mischel, P.S., Stokoe, D., Pieper, R.O., Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 13 (2007), 84–88.
51. [51] Xu, C., Fillmore, C.M., Koyama, S., Wu, H., Zhao, Y., Chen, Z., Herter-Sprie, G.S., Akbay, E.A., Tchaicha, J.H., Altabef, A., Reibel, J.B., Walton, Z., Ji, H., Watanabe, H., Janne, P.A., Castrillon, D.H., Rustgi, A.K., Bass, A.J., Freeman, G.J., Padera, R.F., Dranoff, G., Hammerman, P.S., Kim, C.F., Wong, K.K., Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 25 (2014), 590–604.
52. [52] Koyama, S., Akbay, E.A., Li, Y.Y., Aref, A.R., Skoulidis, F., Herter-Sprie, G.S., Buczkowski, K.A., Liu, Y., Awad, M.M., Denning, W.L., Diao, L., Wang, J., Parra-Cuentas, E.R., Wistuba, I.I., Soucheray, M., Thai, T., Asahina, H., Kitajima, S., Altabef, A., Cavanaugh, J.D., Rhee, K., Gao, P., Zhang, H., Fecci, P.E., Shimamura, T., Hellmann, M.D., Heymach, J.V., Hodi, F.S., Freeman, G.J., Barbie, D.A., Dranoff, G., Hammerman, P.S., Wong, K.K., STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 76 (2016), 999–1008.
53. [53] Skoulidis, F., Byers, L.A., Diao, L., Papadimitrakopoulou, V.A., Tong, P., Izzo, J., Behrens, C., Kadara, H., Parra, E.R., Canales, J.R., Zhang, J., Giri, U., Gudikote, J., Cortez, M.A., Yang, C., Fan, Y., Peyton, M., Girard, L., Coombes, K.R., Toniatti, C., Heffernan, T.P., Choi, M., Frampton, G.M., Miller, V., Weinstein, J.N., Herbst, R.S., Wong, K.K., Zhang, J., Sharma, P., Mills, G.B., Hong, W.K., Minna, J.D., Allison, J.P., Futreal, A., Wang, J., Wistuba, I.I., Heymach, J.V., Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5 (2015), 860–877.
54. [54] Davis, F.M., Stewart, T.A., Thompson, E.W., Monteith, G.R., Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol. Sci. 35 (2014), 479–488.
55. [55] Chen, L., Gibbons, D.L., Goswami, S., Cortez, M.A., Ahn, Y.H., Byers, L.A., Zhang, X., Yi, X., Dwyer, D., Lin, W., Diao, L., Wang, J., Roybal, J.D., Patel, M., Ungewiss, C., Peng, D., Antonia, S., Mediavilla-Varela, M., Robertson, G., Jones, S., Suraokar, M., Welsh, J.W., Erez, B., Wistuba, I.I., Chen, L., Peng, D., Wang, S., Ullrich, S.E., Heymach, J.V., Kurie, J.M., Qin, F.X., Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat. Commun., 5, 2014, 5241.
56. [56] Lou, Y., Diao, L., Parra Cuentas, E.R., Denning, W.L., Chen, L., Fan, Y.H., Byers, L.A., Wang, J., Papadimitrakopoulou, V.A., Behrens, C., Rodriguez, J., Hwu, P., Wistuba, I.I., Heymach, J.V., Gibbons, D.L., Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clin. Cancer Res., 2016.
57. [57] Rizvi NA, Brahmer JR, Ou SI, Segal NH, Khleif S, Hwu WJ, Gutierrez M, Schoffski P, Hamid O, Weiss J, Lutzky J, Maio M, Nemunaitis JJ, Jaeger D, Balmanoukian AS, Rebelatto M, Steele K, Li X, Blake-Haskins JA, Antonia SJ. Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 2015; 33 (suppl 15): abst 8032.
58. [58] Zielinski, C., Knapp, S., Mascaux, C., Hirsch, F., Rationale for targeting the immune system through checkpoint molecule blockade in the treatment of non-small-cell lung cancer. Ann. Oncol. 24 (2013), 1170–1179.
59. [59] Yoshida, N., Abe, H., Ohkuri, T., Wakita, D., Sato, M., Noguchi, D., Miyamoto, M., Morikawa, T., Kondo, S., Ikeda, H., Nishimura, T., Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens and T cell infiltration in non-small cell lung carcinoma and their prognostic significance. Int. J. Oncol. 28 (2006), 1089–1098.
60. [60] Shigematsu, Y., Hanagiri, T., Shiota, H., Kuroda, K., Baba, T., Mizukami, M., So, T., Ichiki, Y., Yasuda, M., So, T., Takenoyama, M., Yasumoto, K., Clinical significance of cancer/testis antigens expression in patients with non-small cell lung cancer. Lung Cancer 68 (2010), 105–110.
61. [61] Besse B, M., J Jänne PA Garassino M Eberhardt WE Peters S Toh CK Kurata T Li Z Kowanetz M Mocci S Sandler A Rizvi NA. Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC). In presented at 2015 European Cancer Congress; 25 September-29 September 2015; Late-Breaking Abstract 16. Vienna, Austria.
62. [62] Govindan, R., Ding, L., Griffith, M., Subramanian, J., Dees, N.D., Kanchi, K.L., Maher, C.A., Fulton, R., Fulton, L., Wallis, J., Chen, K., Walker, J., McDonald, S., Bose, R., Ornitz, D., Xiong, D., You, M., Dooling, D.J., Watson, M., Mardis, E.R., Wilson, R.K., Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150 (2012), 1121–1134.
63. [63] Vogelstein, B., Papadopoulos, N., Velculescu, V.E., Zhou, S., Diaz, L.A. Jr., Kinzler, K.W., Cancer genome landscapes. Science 339 (2013), 1546–1558.
64. [64] Garrido, F., Cabrera, T., Aptsiauri, N., Hard and soft lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int. J. Cancer 127 (2010), 249–256.
65. [65] Chow, M.T., Moller, A., Smyth, M.J., Inflammation and immune surveillance in cancer. Semin. Cancer Biol. 22 (2012), 23–32.
66. [66] Zou, W., Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6 (2006), 295–307.
67. [67] Talmadge, J.E., Gabrilovich, D.I., History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13 (2013), 739–752.
68. [68] Thomas, A., Giaccone, G., Why has active immunotherapy not worked in lung cancer. Ann. Oncol. 26 (2015), 2213–2220.
69. [69] Woo, E.Y., Yeh, H., Chu, C.S., Schlienger, K., Carroll, R.G., Riley, J.L., Kaiser, L.R., June, C.H., Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J. Immunol. 168 (2002), 4272–4276.
70. [70] Wolf, A.M., Wolf, D., Steurer, M., Gastl, G., Gunsilius, E., Grubeck-Loebenstein, B., Increase of regulatory T cells in the peripheral blood of cancer patients. Clin. Cancer Res. 9 (2003), 606–612.
71. [71] Sakaguchi, S., Yamaguchi, T., Nomura, T., Ono, M., Regulatory T cells and immune tolerance. Cell 133 (2008), 775–787.
72. [72] Nishikawa, H., Sakaguchi, S., Regulatory, T., cells in tumor immunity. Int. J. Cancer 127 (2010), 759–767.
73. [73] deLeeuw, R.J., Kost, S.E., Kakal, J.A., Nelson, B.H., The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin. Cancer Res. 18 (2012), 3022–3029.
74. [74] Wolf D, Wolf AM. CCR 20th Anniversary Commentary: From Regulatory T Cells to Checkpoint Monoclonal Antibodies–Immuno-oncology Advances Clinical Cancer Research. Clin Cancer Res 2015;21: 2657–2659.
75. [75] Gabrilovich, D.I., Nagaraj, S., Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9 (2009), 162–174.
76. [76] Ostrand-Rosenberg, S., Sinha, P., Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182 (2009), 4499–4506.
77. [77] Srivastava, M.K., Zhu, L., Harris-White, M., Kar, U.K., Huang, M., Johnson, M.F., Lee, J.M., Elashoff, D., Strieter, R., Dubinett, S., Sharma, S., Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS One, 7, 2012, e40677.