nach oben

Erschienen in:

05.09.2019 | Original Article

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer

verfasst von: Yuping D. Li, Jonathan B. Lamano, Jason B. Lamano, Jessica Quaggin-Smith, Dorina Veliceasa, Gurvinder Kaur, Dauren Biyashev, Dusten Unruh, Orin Bloch

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 9/2019

Einloggen, um Zugang zu erhalten

Abstract

Introduction

Brain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis.

Methods

Peripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation.

Results

Patients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression.

Conclusions

The frequency of PD-L1⁺ myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1⁺ myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.

Nur mit Berechtigung zugänglich

Li Y, Lamano J, Lamano JB, Veliceasa D, Kaur G et al (2018) Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer. J Neurosurg 128(4):961–1272CrossRef

Siegel RL, Miller KD, Jemal A (2017) Cancer statistics. CA Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387 CrossRefPubMed

Alberg AJ, Ford JG, Samet JM (2007) Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). 3 Suppl 132:29–55. https://doi.org/10.1378/chest.07-1347 CrossRef

Schouten LJ, Rutten J, Huveneers HA, Twijnstra A (2002) Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94(10):2698–2705CrossRefPubMed

Arvold ND, Lee EQ, Mehta MP, Margolin K, Alexander BM, Lin NU, Anders CK, Soffietti R, Camidge DR, Vogelbaum MA, Dunn IF, Wen PY (2016) Updates in the management of brain metastases. Neuro Oncol 18(8):1043–1065. https://doi.org/10.1093/neuonc/now127 CrossRefPubMedPubMedCentral

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 373(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643 CrossRefPubMedPubMedCentral

Massarelli E, Papadimitrakopoulou V, Welsh J, Tang C, Tsao AS (2014) Immunotherapy in lung cancer. Transl Lung Cancer Res 3(1):53–63. https://doi.org/10.3978/j.issn.2218-6751.2014.01.01 CrossRefPubMedPubMedCentral

Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. https://doi.org/10.1038/nrc3239 CrossRefPubMedPubMedCentral

Brahmer JR, Hammers H, Lipson EJ (2015) Nivolumab: targeting PD-1 to bolster antitumor immunity. Future Oncol 11(9):1307–1326. https://doi.org/10.2217/fon.15.52 CrossRefPubMed

10.

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WEE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén 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. https://doi.org/10.1056/NEJMoa1504627 CrossRefPubMedPubMedCentral

11.

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 (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028. https://doi.org/10.1056/NEJMoa1501824 CrossRefPubMed

12.

Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, McDermott DF, Pardoll DM, Sankar V, Ahlers CM, Salvati M, Wigginton JM, Hellmann MD, Kollia GD, Gupta AK, Brahmer JR (2015) 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(18):2004–2012. https://doi.org/10.1200/jco.2014.58.3708 CrossRefPubMedPubMedCentral

13.

Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han J-Y, Molina J, Kim J-H, Arvis CD, Ahn M-J, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. The Lancet 387(10027):1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7 CrossRef

14.

Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301. https://doi.org/10.1056/NEJMoa1716948 CrossRefPubMed

15.

Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim Y-C, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Özgüroğlu M (2017) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377(20):1919–1929. https://doi.org/10.1056/NEJMoa1709937 CrossRefPubMed

16.

Lee JY, Chong S, Choi YH, Phi JH, Cheon JE, Kim SK, Park SH, Kim IO, Wang KC (2017) Modification of surgical procedure for “probable” limited dorsal myeloschisis. J Neurosurg Pediatr 19(5):616–619. https://doi.org/10.3171/2016.12.PEDS16171 CrossRefPubMed

17.

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. https://doi.org/10.1016/s1470-2045(15)70054-9 CrossRefPubMedPubMedCentral

18.

Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998. https://doi.org/10.1038/ni1102-991 CrossRefPubMed

19.

Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296. https://doi.org/10.1146/annurev.immunol.25.022106.141609 CrossRefPubMedPubMedCentral

20.

Huang A, Zhang B, Wang B, Zhang F, Fan KX, Guo YJ (2013) Increased CD14(+)HLA-DR (–/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol Immunother 62(9):1439–1451. https://doi.org/10.1007/s00262-013-1450-6 CrossRefPubMed

21.

Vetsika E-K, Koinis F, Gioulbasani M, Aggouraki D, Koutoulaki A, Skalidaki E, Mavroudis D, Georgoulias V, Kotsakis A (2014) A circulating subpopulation of monocytic myeloid-derived suppressor cells as an independent prognostic/predictive factor in untreated non-small lung cancer patients. J Immunol Res 2014:12. https://doi.org/10.1155/2014/659294 CrossRef

22.

Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT (2013) Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res 19(12):3165–3175. https://doi.org/10.1158/1078-0432.CCR-12-3314 CrossRefPubMedPubMedCentral

23.

Bloch O, Lim M, Sughrue ME, Komotar RJ, Abrahams JM, O’Rourke DM, D’Ambrosio A, Bruce JN, Parsa AT (2017) Autologous heat shock protein peptide vaccination for newly diagnosed glioblastoma: impact of peripheral PD-L1 expression on response to therapy. Clin Cancer Res 23(14):3575–3584. https://doi.org/10.1158/1078-0432.Ccr-16-1369 CrossRefPubMedPubMedCentral

24.

Kotsakis A, Koinis F, Katsarou A, Gioulbasani M, Aggouraki D, Kentepozidis N, Georgoulias V, Vetsika EK (2016) Prognostic value of circulating regulatory T cell subsets in untreated non-small cell lung cancer patients. Sci Rep 6:39247. https://doi.org/10.1038/srep39247 CrossRefPubMedPubMedCentral

25.

Lamano J, Lamano J, Choy W, Veliceasa D, DiDomenico J, Oyon D, Quaggin-Smith J, Fakurnejad S, Ampie L, Li D, Kesavabhotla K, Kaur R, James CD, Parsa A, Bloch O (2017) IMMU-38. glioblastoma-derived IL-6 induces immunosuppressive peripheral myeloid cell PD-L1 expression and tumor progression. Neuro-Oncol 19(suppl_6):vi120–vi121. https://doi.org/10.1093/neuonc/nox168.496 CrossRefPubMedCentral

26.

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1. https://doi.org/10.1126/scisignal.2004088 CrossRefPubMedPubMedCentral

27.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404. https://doi.org/10.1158/2159-8290.Cd-12-0095 CrossRefPubMed

28.

Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, Carbone DP, Gabrilovich DI (2000) Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res 6(5):1755–1766PubMed

29.

Gajewski TF, Meng Y, Harlin H (2006) Immune suppression in the tumor microenvironment. J Immunother 29(3):233–240. https://doi.org/10.1097/01.cji.0000199193.29048.56 CrossRefPubMed

30.

Remark R, Becker C, Gomez JE, Damotte D, Dieu-Nosjean M-C, Sautès-Fridman C, Fridman W-H, Powell CA, Altorki NK, Merad M, Gnjatic S (2015) The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med 191(4):377–390. https://doi.org/10.1164/rccm.201409-1671pp CrossRefPubMedPubMedCentral

31.

Chae M, Peterson TE, Balgeman A, Chen S, Zhang L, Renner DN, Johnson AJ, Parney IF (2015) Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model. Neuro Oncol 17(7):978–991. https://doi.org/10.1093/neuonc/nou343 CrossRefPubMed

32.

Gustafson MP, Lin Y, New KC, Bulur PA, O’Neill BP, Gastineau DA, Dietz AB (2010) Systemic immune suppression in glioblastoma: the interplay between CD14(+)HLA-DR(lo/neg) monocytes, tumor factors, and dexamethasone. Neuro-Oncol 12(7):631–644. https://doi.org/10.1093/neuonc/noq001 CrossRefPubMedPubMedCentral

33.

Vuk-Pavlovic S, Bulur PA, Lin Y, Qin R, Szumlanski CL, Zhao X, Dietz AB (2010) Immunosuppressive CD14⁺ HLA-DRlow/- monocytes in prostate cancer. Prostate 70(4):443–455. https://doi.org/10.1002/pros.21078 CrossRefPubMedPubMedCentral

34.

Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169(5):2756–2761CrossRefPubMed

35.

Yu H, Boyle TA, Zhou C, Rimm DL, Hirsch FR (2016) PD-L1 expression in lung cancer. J Thorac Oncol 11(7):964–975CrossRefPubMedPubMedCentral

36.

Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800. https://doi.org/10.1038/nm730 CrossRefPubMed

37.

Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Bronneke HS, Estevez E, Allen TL, Mesaros A, Partridge L, Febbraio MA, Chawla A, Wunderlich FT, Bruning JC (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15(5):423–430. https://doi.org/10.1038/ni.2865 CrossRefPubMedPubMedCentral

38.

Haura EB, Livingston S, Coppola D (2006) Autocrine interleukin-6/interleukin-6 receptor stimulation in non-small-cell lung cancer. Clin Lung Cancer 7(4):273–275CrossRefPubMed

39.

Caetano MS, Zhang H, Cumpian AM, Gong L, Unver N, Ostrin EJ, Daliri S, Chang SH, Ochoa CE, Hanash S, Behrens C, Wistuba II, Sternberg C, Kadara H, Ferreira CG, Watowich SS, Moghaddam SJ (2016) IL6 blockade reprograms the lung tumor microenvironment to limit the development and progression of K-ras-mutant lung cancer. Cancer Res 76(11):3189–3199. https://doi.org/10.1158/0008-5472.Can-15-2840 CrossRefPubMedPubMedCentral

40.

Song L, Smith MA, Doshi P, Sasser K, Fulp W, Altiok S, Haura EB (2014) Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer. J Thorac Oncol 9(7):974–982. https://doi.org/10.1097/JTO.0000000000000193 CrossRefPubMedPubMedCentral

41.

Bichsel CA, Wang L, Froment L, Berezowska S, Müller S, Dorn P, Marti TM, Peng R-W, Geiser T, Schmid RA, Guenat OT, Hall SRR (2017) Increased PD-L1 expression and IL-6 secretion characterize human lung tumor-derived perivascular-like cells that promote vascular leakage in a perfusable microvasculature model. Sci Rep 7(1):10636. https://doi.org/10.1038/s41598-017-09928-1 CrossRefPubMedPubMedCentral

42.

Jayatilaka H, Tyle P, Chen JJ, Kwak M, Ju J, Kim HJ, Lee JSH, Wu P-H, Gilkes DM, Fan R, Wirtz D (2017) Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration. Nat Commun 8:15584. https://doi.org/10.1038/ncomms15584 CrossRefPubMedPubMedCentral

43.

Shen MJ, Xu LJ, Yang L, Tsai Y, Keng PC, Chen Y, Lee SO, Chen Y (2017) Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway. Oncotarget 8(46):80506–80520. https://doi.org/10.18632/oncotarget.19193 CrossRefPubMedPubMedCentral

44.

Kim M-Y, Oskarsson T, Acharyya S, Nguyen DX, Zhang XHF, Norton L, Massagué J (2009) Tumor self-seeding by circulating cancer cells. Cell 139(7):1315–1326. https://doi.org/10.1016/j.cell.2009.11.025 CrossRefPubMedPubMedCentral

45.

De Vita F, Orditura M, Auriemma A, Infusino S, Roscigno A, Catalano G (1998) Serum levels of interleukin-6 as a prognostic factor in advanced non-small cell lung cancer. Oncol Rep 5(3):649–652PubMed

46.

Hao CC, Fu HC, Min YY, Chen CG, Huang TY, Min CY, Shyan HM, Ling CH, Jen LY, Chyr YP, Jen CC, Hsiung CA, Chou SW (2013) Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. Int J Cancer 132(9):1977–1985. https://doi.org/10.1002/ijc.27892 CrossRef

47.

Silva EM, Mariano VS, Pastrez PRA, Pinto MC, Castro AG, Syrjanen KJ, Longatto-Filho A (2017) High systemic IL-6 is associated with worse prognosis in patients with non-small cell lung cancer. PLoS One 12(7):e0181125. https://doi.org/10.1371/journal.pone.0181125 CrossRefPubMedPubMedCentral

Titel: Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer
verfasst von: Yuping D. Li
Jonathan B. Lamano
Jason B. Lamano
Jessica Quaggin-Smith
Dorina Veliceasa
Gurvinder Kaur
Dauren Biyashev
Dusten Unruh
Orin Bloch
Publikationsdatum: 05.09.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 9/2019
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-019-02384-y

Neu im Fachgebiet Onkologie

18.04.2024 | Wirbelsäulenmetastase | Nachrichten

Springer Medizin

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer

Abstract

Introduction

Methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Manche Gestagene können das Risiko für Meningeome erhöhen

Einladung zum PSA-Screening senkt die Krebssterblichkeit

Update Onkologie

Springer Medizin

Abstract

Introduction

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 9/2019

Melanoma-conditioned medium promotes cytotoxic immune responses by murine bone marrow-derived monocytes despite their expression of ‘M2’ markers

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma

Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials

Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells

Lymphocyte-specific kinase expression is a prognostic indicator in ovarian cancer and correlates with a prominent B cell transcriptional signature

Morphomolecular analysis of the immune tumor microenvironment in human head and neck cancer

Neu im Fachgebiet Onkologie

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Manche Gestagene können das Risiko für Meningeome erhöhen

Einladung zum PSA-Screening senkt die Krebssterblichkeit

Update Onkologie