Journal of Neuro-Oncology

, Volume 130, Issue 1, pp 19–29 | Cite as

Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC)

  • Anna Sophie Berghoff
  • Gerda Ricken
  • Dorothee Wilhelm
  • Orsolya Rajky
  • Georg Widhalm
  • Karin Dieckmann
  • Peter Birner
  • Rupert Bartsch
  • Matthias Preusser
Laboratory Investigation


Brain metastases (BM) are frequent in small cell lung cancer (SCLC). Novel insights into their pathobiology are needed for development of better therapies. We investigated tumor-infiltrating lymphocyte (TIL) subsets (CD3+, CD8+, CD45RO+, FOXP3+ and PD-1+) and expression of PD-L1 in a series of 32 SCLC BM specimens and four matched primary tumor specimens using immunohistochemistry. 30/32 (93.8 %) BM specimens showed TIL infiltration. CD3+ TILs were observed in 30/32 (93.8 %) BM specimens, CD8+ TILs in 25/32 (78.1 %), CD45RO+ TILs in 15/32 (46.9 %), FOXP3+ TILs in 15/32 (46.9 %) and PD-1+ TILs in 1/32 (3.1 %) BM specimens. Patients with infiltration of CD45RO+ TILS had a significantly longer median survival time (11 months; 95 % CI 0.000–26.148) as compared to patients without the presence of CD45RO+ TILs (5 months; 95 % CI 0.966–9.034; p = 0.007; log rank test). Membranous PD-L1 on tumor cells was observed in 24/32 (75.0 %) BM specimens, with 11/32 (34.4 %) cases showing PD-L1 expression in over 5 % of viable BM tumor cells. PD-L1 expression on TILs was seen in 8/32 (25.0 %) and on tumor infiltrating macrophages in 9/32 (28.1 %) cases. Patients with PD-L1 expression on TILs presented with improved survival prognosis (6 versus 29 months; p = 0.002; log rank test). Among matched primary tumors, all (4/4; 100 %) specimens showed TIL infiltration, while PD-L1 expression found in only 1/4 (25.0 %) specimen. TIL infiltration and PD-L1 expression are commonly found in SCLC BM and presence of CD45RO+ memory T-cells and PD-L1+ TILs in SCLC BM seem to associate with favorable survival times. Our data suggest an active immune microenvironment in SCLC BM that may be targetable by immune-modulating drugs.


Small cell lung cancer Brain metastases Tumor infiltrating lymphocytes PD-L1 expression Immune checkpoint inhibitor 



We thank Dr. Lieping Chen (Yale) for providing anti-PD-L1 antibody (5H1) for this study. We thank Franziska Vogler, Philip Kresl and Tobias Raymann for excellence technical assistance.


The costs for this project were covered by the research budget of the Medical University of Vienna and the grant “Initiative Krebsforschung” with the project title “Tumorimmunologie von Hirnmetastasen”.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

11060_2016_2216_MOESM1_ESM.tif (10.4 mb)
Supplemental Fig. 1: Control tissue staining results A Immunohistochemistry for PD1 in a lymph node (magnification ×200) B Immunohistochemistry for PD1 in placenta (magnification ×200 ). (TIF 10614 KB)
11060_2016_2216_MOESM2_ESM.tif (5.8 mb)
Supplemental Fig. 2: A PD-L1 expression in macrophages (errors indicate macrophages; magnification ×200 ) B PD-L1 expression in tumor infiltrating lymphocytes (errors indicate TILs; magnification ×200 ) C CD3+ TILs in the same specimen shown in B (magnification ×200 ). (TIF 5907 KB)
11060_2016_2216_MOESM3_ESM.doc (54 kb)
Supplementary material 3 (DOC 53 KB)


  1. 1.
    Antonia S, Bendell J, Taylor M, Calvo E, Jaeger D, De Braud F, Ott P, Pietanza M, Horn L, Le D, Morse M, Lopez-Martin J, Ascierto P, Christensen O, Grosso J, Simon J, Lin C, Eder J (2015) Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol 33(15_suppl):abstr 7503Google Scholar
  2. 2.
    Bender R, Lange S (2001) Adjusting for multiple testing—when and how? J Clin Epidemiol 54(4):343–349PubMedCrossRefGoogle Scholar
  3. 3.
    Berghoff A, Schur S, Füreder L, Gatterbauer B, Dieckmann K, Widhalm G, Hainfellner J, Zielinski C, Birner P, Bartsch R, Preusser M (2016) Descriptive statistical analysis of a real life cohort of 2419 patients with brain metastases of solid cancers. ESMO Open 1. doi: 10.1136/esmoopen-2015-000024 Google Scholar
  4. 4.
    Berghoff A, Fuchs E, Ricken G, Mlecnik B, Bindea G, Spanberger T, Hackl M, Widhalm G, Dieckmann K, Prayer D, Bilocq A, Heinzl H, Zielinski C, Bartsch R, Birner P, Galon J, Preusser M (2016) Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology 5(1):e105738CrossRefGoogle Scholar
  5. 5.
    Berghoff AS, Capper D, Preusser M (2013) Lack of BRAF V600E protein expression in primary central nervous system lymphoma. Appl Immunohistochem Mol Morphol 21(4):351–353. doi: 10.1097/PAI.0b013e3182688e59 PubMedCrossRefGoogle Scholar
  6. 6.
    Berghoff AS, Fuchs E, Ricken G, Mlecnik B, Bindea G, Spanberger T, Hackl M, Widhalm G, Dieckmann K, Prayer D, Bilocq A, Heinzl H, Zielinski C, Bartsch R, Birner P, Galon J, Preusser M (2016) Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology. doi: 10.1080/2162402X.2015.1057388 PubMedGoogle Scholar
  7. 7.
    Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, Dieckmann K, Filipits M, Brandstetter A, Weller M, Kurscheid S, Hegi ME, Zielinski CC, Marosi C, Hainfellner JA, Preusser M, Wick W (2014) Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. doi: 10.1093/neuonc/nou307 PubMedGoogle Scholar
  8. 8.
    Berghoff AS, Preusser M (2015) The inflammatory microenvironment in brain metastases: potential treatment target? Chin Clin Oncol 4(2):21. doi: 10.3978/j.issn.2304-3865.2015.06.03 PubMedGoogle Scholar
  9. 9.
    Berghoff AS, Ricken G, Widhalm G, Rajky O, Dieckmann K, Birner P, Bartsch R, Holler C, Preusser M (2014) Tumor infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology. doi: 10.1111/his.12537 Google Scholar
  10. 10.
    Berghoff AS, Ricken G, Widhalm G, Rajky O, Hainfellner JA, Birner P, Raderer M, Preusser M (2014) PD1 (CD279) and PD-L1 (CD274, B7H1) expression in primary central nervous system lymphomas (PCNSL). Clin Neuropathol 33(1):42–49PubMedCrossRefGoogle Scholar
  11. 11.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. doi: 10.1056/NEJMoa1507643 PubMedGoogle Scholar
  12. 12.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135. doi: 10.1056/NEJMoa1504627 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Buque A, Bloy N, Aranda F, Castoldi F, Eggermont A, Cremer I, Fridman WH, Fucikova J, Galon J, Marabelle A, Spisek R, Tartour E, Zitvogel L, Kroemer G, Galluzzi L (2015) Trial watch: immunomodulatory monoclonal antibodies for oncological indications. Oncoimmunology 4(4):e1008814. doi: 10.1080/2162402X.2015.1008814 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Capper D, Preusser M, Habel A, Sahm F, Ackermann U, Schindler G, Pusch S, Mechtersheimer G, Zentgraf H, von Deimling A (2011) Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol 122(1):11–19. doi: 10.1007/s00401-011-0841-z PubMedCrossRefGoogle Scholar
  15. 15.
    Capper D, Berghoff AS, Magerle M, Ilhan A, Wohrer A, Hackl M, Pichler J, Pusch S, Meyer J, Habel A, Petzelbauer P, Birner P, von Deimling A, Preusser M (2012) Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. Acta Neuropathol 123(2):223–233. doi: 10.1007/s00401-011-0887-y PubMedCrossRefGoogle Scholar
  16. 16.
    Chen DS, Irving BA, Hodi FS (2012) Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 18(24):6580–6587. doi: 10.1158/1078-0432.CCR-12-1362 PubMedCrossRefGoogle Scholar
  17. 17.
    Dahlin AM, Henriksson ML, Van Guelpen B, Stenling R, Oberg A, Rutegard J, Palmqvist R (2011) Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor. Mod Pathol 24(5):671–682. doi: 10.1038/modpathol.2010.234 PubMedCrossRefGoogle Scholar
  18. 18.
    Darb-Esfahani S, Kunze CA, Kulbe H, Sehouli J, Wienert S, Lindner J, Budczies J, Bockmayr M, Dietel M, Denkert C, Braicu I, Johrens K (2016) Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. Oncotarget 7(2):1486–1499. doi: 10.18632/oncotarget.6429 PubMedGoogle Scholar
  19. 19.
    Durand-Panteix S, Farhat M, Youlyouz-Marfak I, Rouaud P, Ouk-Martin C, David A, Faumont N, Feuillard J, Jayat-Vignoles C (2012) B7-H1, which represses EBV-immortalized B cell killing by autologous T and NK cells, is oppositely regulated by c-Myc and EBV latency III program at both mRNA and secretory lysosome levels. J Immunol 189(1):181–190. doi: 10.4049/jimmunol.1102277 PubMedCrossRefGoogle Scholar
  20. 20.
    Foster NR, Qi Y, Shi Q, Krook JE, Kugler JW, Jett JR, Molina JR, Schild SE, Adjei AA, Mandrekar SJ (2011) Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials. Cancer 117(6):1262–1271. doi: 10.1002/cncr.25526 PubMedCrossRefGoogle Scholar
  21. 21.
    Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306. doi: 10.1038/nrc3245 PubMedCrossRefGoogle Scholar
  22. 22.
    Fruh M, De Ruysscher D, Popat S, Crino L, Peters S, Felip E, ESMO Guidelines Working Group (2013) Small-cell lung cancer (SCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 24(suppl 6):vi99–105. doi: 10.1093/annonc/mdt178 PubMedGoogle Scholar
  23. 23.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964. doi: 10.1126/science.1129139 PubMedCrossRefGoogle Scholar
  24. 24.
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, KEYNOTE-001 Investigators (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. doi: 10.1056/NEJMoa1501824 Google Scholar
  25. 25.
    Goldberg S, Gettinger S, Mahajan A, Herbst R, Chiang A, Tsiouris A, Vortmeyer A, Jilaveanu L, Speaker S, Madura M, Rowen E, Gerrish H, Knapp-Perry E, Yao X, Chiang V, Kluger H (2015) Activity and safety of pembrolizumab in patients with metastatic non-small cell lung cancer with untreated brain metastases. J Clin Oncol 33(15_suppl):abstr 8035Google Scholar
  26. 26.
    Hotta K, Sho M, Fujimoto K, Shimada K, Yamato I, Anai S, Konishi N, Hirao Y, Nonomura K, Nakajima Y (2011) Prognostic significance of CD45RO+ memory T cells in renal cell carcinoma. Br J Cancer 105(8):1191–1196. doi: 10.1038/bjc.2011.368 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, Stover E, Strickland KC, D’Andrea AD, Wu CJ, Matulonis UA, Konstantinopoulos PA (2015) Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol 1 (9):1319–1323. doi: 10.1001/jamaoncol.2015.2151 PubMedCrossRefGoogle Scholar
  28. 28.
    Ishii H, Azuma K, Kawahara A, Yamada K, Imamura Y, Tokito T, Kinoshita T, Kage M, Hoshino T (2015) Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol 10(3):426–430. doi: 10.1097/JTO.0000000000000414 PubMedCrossRefGoogle Scholar
  29. 29.
    Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, Alaparthy S, Berman D, Jure-Kunkel M, Siemers NO, Jackson JR, Shahabi V (2012) An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother 61(7):1019–1031. doi: 10.1007/s00262-011-1172-6 PubMedCrossRefGoogle Scholar
  30. 30.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34. doi: 10.1056/NEJMoa1504030 PubMedCrossRefGoogle Scholar
  31. 31.
    Mahoney KM, Sun H, Liao X, Hua P, Callea M, Greenfield EA, Hodi FS, Sharpe AH, Signoretti S, Rodig SJ, Freeman GJ (2015) PD-L1 antibodies to its cytoplasmic domain most clearly delineate cell membranes in immunohistochemical staining of tumor cells. Cancer Immunol Res 3(12):1308–1315. doi: 10.1158/2326-6066.CIR-15-0116 PubMedCrossRefGoogle Scholar
  32. 32.
    Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13(5):459–465. doi: 10.1016/S1470-2045(12)70090-6 PubMedCrossRefGoogle Scholar
  33. 33.
    Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate I (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. doi: 10.1056/NEJMoa1510665 PubMedCentralGoogle Scholar
  34. 34.
    Nugent JL, Bunn PA Jr, Matthews MJ, Ihde DC, Cohen MH, Gazdar A, Minna JD (1979) CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44(5):1885–1893PubMedCrossRefGoogle Scholar
  35. 35.
    Ott P, Fernandez M, Hiret S, Kim D, Moss R, Winser T, Yuan S, Cheng J, Piperdi B, Mehnert J (2015) Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): preliminary safety and efficacy results from KEYNOTE-028. J Clin Oncol 33(15_suppl):abstr 7502Google Scholar
  36. 36.
    Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25):2654–2666. doi: 10.1056/NEJMoa051424 PubMedCrossRefGoogle Scholar
  37. 37.
    Postmus PE, Haaxma-Reiche H, Gregor A, Groen HJ, Lewinski T, Scolard T, Kirkpatrick A, Curran D, Sahmoud T, Giaccone G (1998) Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study. Radiother Oncol 46(1):29–32PubMedCrossRefGoogle Scholar
  38. 38.
    Qu QX, Huang Q, Shen Y, Zhu YB, Zhang XG (2016) The increase of circulating PD-L1-expressing CD68(+) macrophage in ovarian cancer. Tumour Biol 37(4):5031–5037. doi: 10.1007/s13277-015-4066-y PubMedCrossRefGoogle Scholar
  39. 39.
    Rades D, Dziggel L, Segedin B, Oblak I, Nagy V, Marita A, Schild SE (2013) The first survival score for patients with brain metastases from small cell lung cancer (SCLC). Clin Neurol Neurosurg 115(10):2029–2032. doi: 10.1016/j.clineuro.2013.06.019 PubMedCrossRefGoogle Scholar
  40. 40.
    Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS (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):257–265. doi: 10.1016/S1470-2045(15)70054-9 PubMedCrossRefGoogle Scholar
  41. 41.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, 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 IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330. doi: 10.1056/NEJMoa1412082 PubMedCrossRefGoogle Scholar
  42. 42.
    Ross JS, Wang K, Elkadi OR, Tarasen A, Foulke L, Sheehan CE, Otto GA, Palmer G, Yelensky R, Lipson D, Chmielecki J, Ali SM, Elvin J, Morosini D, Miller VA, Stephens PJ (2014) Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer. J Clin Pathol 67(9):772–776. doi: 10.1136/jclinpath-2014-202447 PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, Postmus P, Collette L, Musat E, Senan S, EORTC Radiation Oncology Group, Lung Cancer Group (2007) Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357(7):664–672. doi: 10.1056/NEJMoa071780 PubMedCrossRefGoogle Scholar
  44. 44.
    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199. doi: 10.1056/NEJMoa1406498 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M (2011) Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. doi: 10.1200/JCO.2011.38.0527 PubMedPubMedCentralGoogle Scholar
  46. 46.
    Tan KW, Evrard M, Tham M, Hong M, Huang C, Kato M, Prevost-Blondel A, Donnadieu E, Ng LG, Abastado JP (2015) Tumor stroma and chemokines control T-cell migration into melanoma following Temozolomide treatment. Oncoimmunology 4(2):e978709. doi: 10.4161/2162402X.2014.978709 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA (2014) 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(19):5064–5074. doi: 10.1158/1078-0432.CCR-13-3271 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Teng MW, Swann JB, Koebel CM, Schreiber RD, Smyth MJ (2008) Immune-mediated dormancy: an equilibrium with cancer. J Leukoc Biol 84(4):988–993. doi: 10.1189/jlb.1107774 PubMedCrossRefGoogle Scholar
  49. 49.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi: 10.1056/NEJMoa1200690 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MH, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207–211. doi: 10.1126/science.aad0095 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL (2014) Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 94(1):107–116. doi: 10.1038/labinvest.2013.130 PubMedCrossRefGoogle Scholar
  52. 52.
    Webb JR, Milne K, Kroeger DR, Nelson BH (2016) PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol Oncol 141(2):293–302. doi: 10.1016/j.ygyno.2016.03.008 PubMedCrossRefGoogle Scholar
  53. 53.
    Woehrer A (2013) Brain tumor epidemiology in Austria and the Austrian Brain Tumor Registry. Clin Neuropathol 32(4):269–285. doi: 10.5414/NP300600 PubMedCrossRefGoogle Scholar
  54. 54.
    Wohrer A, Waldhor T, Heinzl H, Hackl M, Feichtinger J, Gruber-Mosenbacher U, Kiefer A, Maier H, Motz R, Reiner-Concin A, Richling B, Idriceanu C, Scarpatetti M, Sedivy R, Bankl HC, Stiglbauer W, Preusser M, Rossler K, Hainfellner JA (2009) The Austrian Brain Tumour Registry: a cooperative way to establish a population-based brain tumour registry. J Neurooncol 95(3):401–411. doi: 10.1007/s11060-009-9938-9 PubMedCrossRefGoogle Scholar
  55. 55.
    Yajima R, Yajima T, Fujii T, Yanagita Y, Fujisawa T, Miyamoto T, Tsutsumi S, Iijima M, Kuwano H (2015) Tumor-infiltrating CD45RO memory cells are associated with a favorable prognosis breast cancer. Breast Cancer. doi: 10.1007/s12282-015-0622-y PubMedGoogle Scholar
  56. 56.
    Zhu H, Bi Y, Han A, Luo J, Li M, Shi F, Kong L, Yu J (2014) Risk factors for brain metastases in completely resected small cell lung cancer: a retrospective study to identify patients most likely to benefit from prophylactic cranial irradiation. Radiat Oncol 9:216. doi: 10.1186/1748-717X-9-216 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74(18):5057–5069. doi: 10.1158/0008-5472.CAN-13-3723 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Anna Sophie Berghoff
    • 1
    • 2
  • Gerda Ricken
    • 2
    • 3
  • Dorothee Wilhelm
    • 4
  • Orsolya Rajky
    • 1
    • 2
  • Georg Widhalm
    • 3
    • 5
  • Karin Dieckmann
    • 2
    • 6
  • Peter Birner
    • 2
    • 7
  • Rupert Bartsch
    • 1
    • 2
  • Matthias Preusser
    • 1
    • 2
  1. 1.Department of Medicine I and Comprehensive Cancer Center CNS Unit (CCC-CNS)Medical University of ViennaViennaAustria
  2. 2.Comprehensive Cancer CenterMedical University of ViennaViennaAustria
  3. 3.Institute of NeurologyMedical University of ViennaViennaAustria
  4. 4.Department for Radiology and Nuclear MedicineMedical University of ViennaViennaAustria
  5. 5.Department of NeurosurgeryMedical University of ViennaViennaAustria
  6. 6.Department of RadiotherapyMedical University of ViennaViennaAustria
  7. 7.Institute of Clinical PathologyMedical University of ViennaViennaAustria

Personalised recommendations