Chemokine profiling in serum from patients with ovarian cancer reveals candidate biomarkers for recurrence and immune infiltration

Mlynska,Agata; Salciuniene,Greta; Zilionyte,Karolina; Garberyte,Sima; Strioga,Marius; Intaite,Birute; Barakauskiene,Ausrine; Lazzari,Gianrocco; Dobrovolskiene,Neringa; Krasko,Jan   Aleksander; Pasukoniene,Vita

doi:10.3892/or.2018.6886

Chemokine profiling in serum from patients with ovarian cancer reveals candidate biomarkers for recurrence and immune infiltration

Authors:
- Agata Mlynska
- Greta Salciuniene
- Karolina Zilionyte
- Sima Garberyte
- Marius Strioga
- Birute Intaite
- Ausrine Barakauskiene
- Gianrocco Lazzari
- Neringa Dobrovolskiene
- Jan Aleksander Krasko
- Vita Pasukoniene
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Affiliations: Laboratory of Immunology, National Cancer Institute, Vilnius LT‑08660, Lithuania, Life Sciences Center, Vilnius University, Vilnius LT‑10257, Lithuania, Swiss Federal Institute of Technology Global Health Institute, Lausanne CH‑1015, Switzerland
Published online on: November 27, 2018 https://doi.org/10.3892/or.2018.6886
Pages: 1238-1252

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Abstract

The management of advanced ovarian cancer is challenging due to the high frequency of recurrence, often associated with the development of resistance to platinum‑based chemotherapy. Molecular analyses revealed the complexity of ovarian cancer with particular emphasis on the immune system, which may contribute to disease progression and response to treatment. Cytokines and chemokines mediate the cross‑talk between cancer and immune cells, and therefore, present as potential biomarkers, reflecting the tumor microenvironment. A panel of circulating C‑C motif chemokine ligand (CCL) and C‑X‑C motif chemokine ligand (CXCL) chemokines were examined in the serum of 40 high‑grade patients with ovarian cancer prior to primary surgery. The level of immune infiltration in tumors was also analyzed. The preoperative levels of chemokines differ between patients. Elevated levels of circulating CXCL4 + CCL20 + CXCL1 combination can discriminate patients with shorter recurrence‑free survival and overall survival. The presence of tumor‑infiltrating T lymphocytes was detected in half of the patients. The mRNA expression analysis suggests the presence of antitumoral and immunosuppressive elements in the tumor microenvironment. The combination of circulating CXCL9 + CXCL10 can distinguish immune‑infiltrated tumors that will lead to shorter recurrence‑free survival. The results suggest that preoperative profiling of circulating chemokines in patients with ovarian cancer may provide valuable information regarding tumor recurrence and immune infiltration. The findings demonstrate that combinations have better prognostic utility than single chemokines, and may serve as patient stratification tools.

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1	Sant M, Allemani C, Santaquilani M, Knijn A, Marchesi F and Capocaccia R: EUROCARE Working Group: EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results and commentary. Eur J Cancer. 45:931–991. 2009. View Article : Google Scholar : PubMed/NCBI
2	Sant M, Chirlaque Lopez MD, Agresti R, Sánchez Perez MJ, Holleczek B, Bielska-Lasota M, Dimitrova N, Innos K, Katalinic A, Langseth H, et al: Survival of women with cancers of breast and genital organs in Europe 1999–2007: Results of the EUROCARE-5 study. Eur J Cancer. 51:2191–2205. 2015. View Article : Google Scholar : PubMed/NCBI
3	Bowtell DD, Böhm S, Ahmed AA, Aspuria PJ, Bast R, Beral V, Berek JS, Birrer MJ, Blagden S, Bookman MA, et al: Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 15:668–679. 2015. View Article : Google Scholar : PubMed/NCBI
4	Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J and Karlan BY: Ovarian cancer. Nat Rev Dis Primers. 2:160612016. View Article : Google Scholar : PubMed/NCBI
5	Friedlander M, Trimble E, Tinker A, Alberts D, Avall-Lundquist E, Brady M, Harter P, Pignata S, Pujade-Lauraine E, Sehouli J, et al: Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer. 21:771–775. 2011. View Article : Google Scholar : PubMed/NCBI
6	Alvarez RD, Matulonis UA, Herzog TJ, Coleman RL, Monk BJ and Markman M: Moving beyond the platinum sensitive/resistant paradigm for patients with recurrent ovarian cancer. Gynecol Oncol. 141:405–409. 2016. View Article : Google Scholar : PubMed/NCBI
7	Bell D, Berchuck A, Birrer M, Chien J, Cramer D, Dao F, Dhir R, DiSala P, Gabra H, Glenn P, et al: Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar : PubMed/NCBI
8	Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, Johnson DS, Trivett MK, Etemadmoghadam D, Locandro B, et al: Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res. 14:5198–5208. 2008. View Article : Google Scholar : PubMed/NCBI
9	Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, Fereday S, Lawrence M, Carter SL, Mermel CH, et al: Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest. 123:517–525. 2013.PubMed/NCBI
10	Konecny GE, Wang C, Hamidi H, Winterhoff B, Kalli KR, Dering J, Ginther C, Chen HW, Dowdy S, Cliby W, et al: Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. J Natl Cancer Inst. 106(pii): dju2492014.PubMed/NCBI
11	Nelson BH: New insights into tumor immunity revealed by the unique genetic and genomic aspects of ovarian cancer. Curr Opin Immunol. 33:93–100. 2015. View Article : Google Scholar : PubMed/NCBI
12	Hwang WT, Adams SF, Tahirovic E, Hagemann IS and Coukos G: Prognostic significance of tumor-infiltrating T cells in ovarian cancer: A meta-analysis. Gynecol Oncol. 124:192–198. 2012. View Article : Google Scholar : PubMed/NCBI
13	Hao D, Liu J, Chen M, Li J, Wang L, Li X, Zhao Q and Di LJ: Immunogenomic analyses of advanced serous ovarian cancer reveal immune score is a prognostic factor and an indicator of chemosensitivity. Clin Cancer Res. 24:3560–3571. 2018. View Article : Google Scholar : PubMed/NCBI
14	Wang W, Kryczek I, Dostál L, Lin H, Tan L, Zhao L, Lu F, Wei S, Maj T, Peng D, et al: Effector T cells abrogate Stroma-mediated chemoresistance in ovarian cancer. Cell. 165:1092–1105. 2016. View Article : Google Scholar : PubMed/NCBI
15	Xu S, Tao Z, Hai B, Liang H, Shi Y, Wang T, Song W, Chen Y, OuYang J, Chen J, et al: miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint. Nat Commun. 7:114062016. View Article : Google Scholar : PubMed/NCBI
16	Rabinovich GA, Gabrilovich D and Sotomayor EM: Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 25:267–296. 2007. View Article : Google Scholar : PubMed/NCBI
17	Castells M, Thibault B, Delord JP and Couderc B: Implication of tumor microenvironment in chemoresistance: Tumor-associated stromal cells protect tumor cells from cell death. Int J Mol Sci. 13:9545–9571. 2012. View Article : Google Scholar : PubMed/NCBI
18	Baghdadi M, Wada H, Nakanishi S, Abe H, Han N, Wira E, Endo D, Watari H, Sakuragi N, Hida Y, et al: Chemotherapy-induced IL34 enhances immunosuppression by tumor-associated macrophages and mediates survival of chemoresistant lung cancer cells. Cancer Res. 76:6030–6042. 2016. View Article : Google Scholar : PubMed/NCBI
19	Takeuchi S, Baghdadi M, Tsuchikawa T, Wada H, Nakamura T, Abe H, Nakanishi S, Usui Y, Higuchi K, Takahashi M, et al: Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res. 75:2629–2640. 2015. View Article : Google Scholar : PubMed/NCBI
20	Mukaida N, Sasaki S and Baba T: Chemokines in cancer development and progression and their potential as targeting molecules for cancer treatment. Mediators Inflamm. 2014:1703812014. View Article : Google Scholar : PubMed/NCBI
21	Gnjatic S, Bronte V, Brunet LR, Butler MO, Disis ML, Galon J, Hakansson LG, Hanks BA, Karanikas V, Khleif SN, et al: Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy. J Immunother Cancer. 5:442017. View Article : Google Scholar : PubMed/NCBI
22	Yang WL, Lu Z and Bast RC Jr: The role of biomarkers in the management of epithelial ovarian cancer. Expert Rev Mol Diagn. 17:577–591. 2017. View Article : Google Scholar : PubMed/NCBI
23	Prat J: FIGO Committee on Gynecologic Oncology: Abridged republication of FIGO's staging classification for cancer of the ovary, fallopian tube, and peritoneum. Cancer. 121:3452–3454. 2015. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^ΔΔ^C^T method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29:e452001. View Article : Google Scholar : PubMed/NCBI
26	Shimizu Y, Kamoi S, Amada S, Akiyama F and Silverberg SG: Toward the development of a universal grading system for ovarian epithelial carcinoma: Testing of a proposed system in a series of 461 patients with uniform treatment and follow-up. Cancer. 82:893–901. 1988. View Article : Google Scholar
27	Kaku T, Ogawa S, Kawano Y, Ohishi Y, Kobayashi H, Hirakawa T and Nakano H: Histological classification of ovarian cancer. Med Electron Microsc. 36:9–17. 2003. View Article : Google Scholar : PubMed/NCBI
28	Mitchell AJ: Sensitivity × PPV is a recognized test called the clinical utility index (CUI+). Eur J Epidemiol. 26:251–252. 2011. View Article : Google Scholar : PubMed/NCBI
29	Charo IF and Ransohoff RM: The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 354:610–621. 2006. View Article : Google Scholar : PubMed/NCBI
30	Pitteri SJ, Kelly-Spratt KS, Gurley KE, Kennedy J, Buson TB, Chin A, Wang H, Zhang Q, Wong CH, Chodosh LA, et al: Tumor microenvironment-derived proteins dominate the plasma proteome response during breast cancer induction and progression. Cancer Res. 71:5090–5100. 2011. View Article : Google Scholar : PubMed/NCBI
31	Gevaert O, De Smet F, Van Gorp T, Pochet N, Engelen K, Amant F, De Moor B, Timmerman D and Vergote I: Expression profiling to predict the clinical behaviour of ovarian cancer fails independent evaluation. BMC Cancer. 8:182008. View Article : Google Scholar : PubMed/NCBI
32	Helleman J, Jansen MP, Span PN, van Staveren IL, Massuger LF, Meijer-van Gelder ME, Sweep FC, Ewing PE, van der Burg ME, Stoter G, et al: Molecular profiling of platinum resistant ovarian cancer. Int J Cancer. 118:1963–1971. 2006. View Article : Google Scholar : PubMed/NCBI
33	Gonzalez Bosquet J, Newtson AM, Chung RK, Thiel KW, Ginader T, Goodheart MJ, Leslie KK and Smith BJ: Prediction of chemo-response in serous ovarian cancer. Mol Cancer. 15:662016. View Article : Google Scholar : PubMed/NCBI
34	Chung RK, Newtson AM, Mott SL and Gonzalez Bosquet J: Clinicopathological predictors of responsiveness in epithelial ovarian cancer: A preliminary institutional study. Proc Obstet Gynecol. 5:62015. View Article : Google Scholar
35	Masoumi-Moghaddam S, Amini A, Wei AQ, Robertson G and Morris DL: Vascular endothelial growth factor expression correlates with serum CA125 and represents a useful tool in prediction of refractoriness to platinum-based chemotherapy and ascites formation in epithelial ovarian cancer. Oncotarget. 6:28491–28501. 2015. View Article : Google Scholar : PubMed/NCBI
36	Angioli R, Capriglione S, Aloisi A, Guzzo F, Luvero D, Miranda A, Damiani P, Montera R, Terranova C and Plotti F: Can HE4 predict platinum response during first-line chemotherapy in ovarian cancer? Tumor Biol. 35:7009–7015. 2014. View Article : Google Scholar
37	Chudecka-Głaz A, Cymbaluk-Płoska A, Wężowska M and Menkiszak J: Could HE4 level measurements during first-line chemotherapy predict response to treatment among ovarian cancer patients? PLoS One. 13:e01942702018. View Article : Google Scholar : PubMed/NCBI
38	Pogge von Strandmann E, Reinartz S, Wager U and Müller R: Tumor-host cell interactions in ovarian cancer: Pathways to therapy failure. Trends Cancer. 3:137–148. 2017. View Article : Google Scholar : PubMed/NCBI
39	Senthebane DA, Rowe A, Thomford NE, Shipanga H, Munro D, Mazeedi MAM, Almazyadi HAM, Kallmeyer K, Dandara C, Pepper MS, et al: The role of tumor microenvironment in chemoresistance: To survive, keep your enemies closer. Int J Mol Sci. 18(pii): E15862017. View Article : Google Scholar : PubMed/NCBI
40	de Visser KE and Jonkers J: Towards understanding the role of cancer-associated inflammation in chemoresistance. Curr Pharm Des. 15:1844–1853. 2009. View Article : Google Scholar : PubMed/NCBI
41	Szajnik M, Szczepanski MJ, Czystowska M, Elishaev E, Mandapathil M, Nowak-Markwitz E, Spaczynski M and Whiteside TL: TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene. 28:4353–4363. 2009. View Article : Google Scholar : PubMed/NCBI
42	Wang Q, Li D, Zhang W, Tang B, Li QQ and Li L: Evaluation of proteomics-identified CCL18 and CXCL1 as circulating tumor markers for differential diagnosis between ovarian carcinomas and benign pelvic masses. Int J Biol Markers. 26:262–273. 2011. View Article : Google Scholar : PubMed/NCBI
43	Bolitho C, Hahn MA, Baxter RC and Marsh DJ: The chemokine CXCL1 induces proliferation in epithelial ovarian cancer cells by transactivation of the epidermal growth factor receptor. Endocr Relat Cancer. 17:929–940. 2010. View Article : Google Scholar : PubMed/NCBI
44	Scapini P, Morini M, Tecchio C, Minghelli S, Di Carlo E, Tanghetti E, Albini A, Lowell C, Berrton G, Noonan DM and Cassatella MA: CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. J Immunol. 172:5034–5040. 2004. View Article : Google Scholar : PubMed/NCBI
45	Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova-Todorova K, Leversha M, Hogg N, Seshan VE, et al: A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell. 150:165–178. 2012. View Article : Google Scholar : PubMed/NCBI
46	Son DS, Kabir SM, Dong Y, Lee E and Adunyah SE: Characteristics of chemokine signatures elicited by EGF and TNF in ovarian cancer cells. J Inflamm. 10:252013. View Article : Google Scholar
47	Marsigliante S, Vetrugno C and Muscella A: CCL20 induces migration and proliferation on breast epithelial cells. J Cell Physiol. 228:1873–1883. 2013. View Article : Google Scholar : PubMed/NCBI
48	Beider K, Abraham M, Begin M, Wald H, Weiss ID, Wald O, Pikarsky E, Abramovitch R, Zeira E, Galun E, et al: Interaction between CXCR4 and CCL20 pathways regulates tumor growth. PLoS One. 4:e51252009. View Article : Google Scholar : PubMed/NCBI
49	Greaves DR, Wang W, Dairaghi DJ, Dieu MC, Saint-Vis B, Franz-Bacon K, Rossi D, Caux C, McClanahan T, Gordon S, et al: CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3α and is highly expressed in human dendritic cells. J Exp Med. 186:837–844. 1997. View Article : Google Scholar : PubMed/NCBI
50	Cook KW, Letley DP, Ingram RJ, Staples E, Skjoldmose H, Atherton JC and Robinson K: CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa. Gut. 63:1550–1559. 2014. View Article : Google Scholar : PubMed/NCBI
51	Liu JY, Li F, Wang LP, Chen XF, Wang D, Cao L, Ping Y, Zhao S, Li B, Thorne SH, et al: CTL- vs T_reg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. Br J Cancer. 113:747–755. 2015. View Article : Google Scholar : PubMed/NCBI
52	Zsiros E, Duttagupta P, Dangaj D, Li H, Frank R, Garrabrant T, Hagemann IS, Levine BL, June CH, Zhang L, et al: The ovarian cancer chemokine landscape is conducive to homing of vaccine-primed and CD3/CD28-costimulated T cells prepared for adoptive therapy. Clin Cancer Res. 21:2840–2850. 2015. View Article : Google Scholar : PubMed/NCBI
53	Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, McSkane M, Baba H and Lenz HJ: CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation-a target for novel cancer therapy. Cancer Treat Rev. 63:40–47. 2018. View Article : Google Scholar : PubMed/NCBI
54	Bronger H, Singer J, Windmüller C, Reuning U, Zech D, Delbridge C, Dorn J, Kiechle M, Schmalfeldt B, Schmitt M and Avril S: CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer. Br J Cancer. 115:553–563. 2016. View Article : Google Scholar : PubMed/NCBI
55	Mir MA, Maurer MJ, Ziesmer SC, Slager SL, Habermann T, Macon WR, Link BK, Syrbu S, Witzig T, Friedberg JW, et al: Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma. Blood. 125:992–998. 2015. View Article : Google Scholar : PubMed/NCBI
56	Flores RJ, Kelly AJ, Li Y, Nakka M, Barkauskas DA, Krailo M, Wang LL, Perlaky L, Lau CC, Hicks MJ, et al: A novel prognostic model for osteosarcoma using circulating CXCL10 and FLT3LG. Cancer. 123:144–154. 2017. View Article : Google Scholar : PubMed/NCBI
57	Hong JY, Ryu KJ, Lee JY, Park C, Ko YH, Kim WS and Kim SJ: Serum level of CXCL10 is associated with inflammatory prognostic biomarkers in patients with diffuse large B-cell lymphoma. Hematol Oncol. 35:480–486. 2017. View Article : Google Scholar : PubMed/NCBI
58	Bai M, Chen X and Ba YI: CXCL10/CXCR3 overexpression as a biomarker of poor prognosis in patients with stage II colorectal cancer. Mol Clin Oncol. 4:23–30. 2016. View Article : Google Scholar : PubMed/NCBI
59	Toiyama Y, Fujikawa H, Kawamura M, Matsushita K, Saigusa S, Tanaka K, Inoue Y, Uchida M, Mohri Y and Kusunoki M: Evaluation of CXCL10 as a novel serum marker for predicting liver metastasis and prognosis in colorectal cancer. Int J Oncol. 40:560–566. 2012.PubMed/NCBI
60	Specht K, Harbeck N, Smida J, Annecke K, Reich U, Naehrig J, Langer R, Mages J, Busch R, Kruse E, et al: Expression profiling identifies genes that predict recurrence of breast cancer after adjuvant CMF-based chemotherapy. Breast Cancer Res Treat. 118:45–56. 2009. View Article : Google Scholar : PubMed/NCBI
61	K Au K, Peterson N, Truesdell P, Reid-Schachter G, Khalaj K, Ren R, Francis JA, Graham CH, Craig AW and Koti M: CXCL10 alters the tumour immune microenvironment and disease progression in a syngeneic murine model of high-grade serous ovarian cancer. Gynecol Oncol. 145:436–445. 2017. View Article : Google Scholar : PubMed/NCBI
62	Redjimi N, Raffin C, Raimbaud I, Pignon P, Matsuzaki J, Odunsi K, Valmori D and Ayyoub M: CXCR3⁺ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res. 72:4351–4360. 2012. View Article : Google Scholar : PubMed/NCBI
63	Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, et al: Intraepithelial CD8⁺ tumor-infiltrating lymphocytes and a high CD8⁺/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 102:18538–18543. 2005. View Article : Google Scholar : PubMed/NCBI
64	Casrouge A, Decalf J, Ahloulay M, Lababidi C, Mansour H, Vallet-Pichard A, Mallet V, Mottez E, Mapes J, Fontanet A, et al: Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV. J Clin Invest. 121:308–317. 2011. View Article : Google Scholar : PubMed/NCBI
65	Rainczuk A, Rao JR, Gathercole JL, Fairweather NJ, Chu S, Masadah R, Jobling TW, Deb-Choudhury S, Dyer J and Stephens AN: Evidence for the antagonistic form of CXC-motif chemokine CXCL10 in serous epithelial ovarian tumours. Int J Cancer. 134:530–541. 2014. View Article : Google Scholar : PubMed/NCBI
66	Ding Q, Lu P, Xia Y, Ding S, Fan Y, Li X, Han P, Liu J, Tian D and Liu M: CXCL9: Evidence and contradictions for its role in tumor progression. Cancer Med. 5:3246–3259. 2016. View Article : Google Scholar : PubMed/NCBI
67	Chen DS and Mellman I: Oncology meets immunology: The cancer-immunity cycle. Immunity. 39:1–10. 2013. View Article : Google Scholar : PubMed/NCBI
68	Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizée G, Radvanyi L, et al: PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res. 72:5209–5218. 2012. View Article : Google Scholar : PubMed/NCBI
69	Bedognetti D, Spivey TL, Zhao Y, Uccellini L, Tomei S, Dudley ME, Ascierto ML, De Giorgi V, Liu Q, Delogu LG, et al: CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2. Br J Cancer. 109:2412–2423. 2013. View Article : Google Scholar : PubMed/NCBI
70	Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M and Gajewski TF: Chemokine expression in melanoma metastases associated with CD8⁺ T-cell recruitment. Cancer Res. 69:3077–3085. 2009. View Article : Google Scholar : PubMed/NCBI
71	Tarhini AA, Lin Y, Lin HM, Vallabhaneni P, Sander C, LaFramboise W and Hamieh L: Expression profiles of immune-related genes are associated with neoadjuvant ipilimumab clinical benefit. Oncoimmunology. 6:e12312912016. View Article : Google Scholar : PubMed/NCBI
72	Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, et al: IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 127:2930–2940. 2017. View Article : Google Scholar : PubMed/NCBI
73	Yamazaki N, Kiyohara Y, Uhara H, Iizuka H, Uehara J, Otsuka F, Fujisawa Y, Takenouchi T, Isei T, Iwatsuki K, et al: Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma. Cancer Sci. 108:1022–1031. 2017. View Article : Google Scholar : PubMed/NCBI
74	Choueiri TK, Fishman MN, Escudier B, McDermott DF, Drake CG, Kluger H, Stadler WM, Perez-Gracia JL, McNeel DG, Curti B, et al: Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin Cancer Res. 22:5461–5471. 2016. View Article : Google Scholar : PubMed/NCBI
75	Hamanishi J, Mandai M and Konishi I: Immune checkpoint inhibition in ovarian cancer. Int Immunol. 28:339–348. 2016. View Article : Google Scholar : PubMed/NCBI
76	Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, Kanai M, Mori Y, Matsumoto S, Chikuma S, et al: Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 33:4015–4022. 2015. View Article : Google Scholar : PubMed/NCBI
77	Coosemans A, Decoene J, Baert T, Laenen A, Kasran A, Verschuere T, Seys S and Vergote I: Immunosuppressive parameters in serum of ovarian cancer patients change during the disease course. Oncoimmunology. 5:e11115052016. View Article : Google Scholar : PubMed/NCBI