Top

Published in:

01-10-2020 | Kidney Cancer | Original Article

Galectin-9 expression as a poor prognostic factor in patients with renal cell carcinoma

Authors: Ryosuke Jikuya, Takeshi Kishida, Masahiko Sakaguchi, Tomoyuki Yokose, Masato Yasui, Akihito Hashizume, Tomoyuki Tatenuma, Nobuhiko Mizuno, Kentaro Muraoka, Susumu Umemoto, Masaki Kawai, Mitsuyo Yoshihara, Yoshiyasu Nakamura, Yohei Miyagi, Tetsuro Sasada

Published in: Cancer Immunology, Immunotherapy | Issue 10/2020

Abstract

Recently, the effectiveness of anti-programmed death 1 (PD-1) antibody therapy in the treatment of renal cell carcinoma (RCC) has been established. Nevertheless, efficacy has been reported to be limited to only 10–30% of patients. To develop more effective immunotherapy for RCC, we analyzed the immunological characteristics in RCC tissues by immunohistochemistry (IHC). We prepared a tissue microarray that consisted of tumor tissue sections (1 mm in diameter) from 83 RCC patients in Kanagawa Cancer Center between 2006 and 2015. IHC analysis was performed with antibodies specific to immune-related (CD8 and Foxp3) and immune checkpoint (programmed death ligand 1 (PD-L1) and 2 (PD-L2), B7-H4 and galectin-9) molecules. The numbers and proportions of positively stained tumor cells or immune cells were determined in each section. From multivariate analysis of all 83 patients, higher galectin-9 expression was detected as a factor associated with worse overall survival (OS) (P = 0.029) and that higher stage and higher B7-H4 expression were associated with worse progression-free survival (PFS) (P < 0.001 and P = 0.021, respectively). Similarly, in multivariate analysis of 69 patients with clear cell RCC, though not statistically significant, there was a trend for association between higher galectin-9 expression and worse OS (P = 0.067), while higher stage was associated with worse PFS (P < 0.001). This study suggests that higher galectin-9 expression is an independent adverse prognostic factor of OS in RCC patients. Therefore, to develop more effective personalized immunotherapy to treat RCC, it may be important to target not only PD-1/PD-L1, but also other immune checkpoint molecules such as galectin-9.

Available only for authorised users

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492CrossRefPubMed

Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690CrossRefPubMedPubMedCentral

Motzer RJ, Rini BI, McDermott DF et al (2015) Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 33:1430–1437. https://doi.org/10.1200/JCO.2014.59.0703CrossRefPubMed

Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813. https://doi.org/10.1056/NEJMoa1510665CrossRefPubMedPubMedCentral

Weber JS, D'Angelo SP, Minor D et al (2015) 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 16:375–384. https://doi.org/10.1016/S1470-2045(15)70076-8CrossRefPubMed

Daud AI, Wolchok JD, Robert C et al (2016) Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 34:4102–4109. https://doi.org/10.1200/JCO.2016.67.2477CrossRefPubMedPubMedCentral

Gandhi L, Rodriguez-Abreu D, Gadgeel S et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078–2092. https://doi.org/10.1056/NEJMoa1801005CrossRefPubMed

Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14:717–734. https://doi.org/10.1038/nrclinonc.2017.101CrossRefPubMed

Giraldo NA, Becht E, Vano Y et al (2017) Tumor-infiltrating and peripheral blood T-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin Cancer Res 23:4416–4428. https://doi.org/10.1158/1078-0432.CCR-16-2848CrossRefPubMed

10.

Tanaka A, Sakaguchi S (2017) Regulatory T cells in cancer immunotherapy. Cell Res 27:109–118. https://doi.org/10.1038/cr.2016.151CrossRefPubMed

11.

Polimeno M, Napolitano M, Costantini S et al (2013) Regulatory T cells, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), CXCL10, CXCL11, epidermal growth factor (EGF) and hepatocyte growth factor (HGF) as surrogate markers of host immunity in patients with renal cell carcinoma. BJU Int 112:686–696. https://doi.org/10.1111/bju.12068CrossRefPubMed

12.

Leite KR, Reis ST, Junior JP, Zerati M, Gomes Dde O, Camara-Lopes LH, Srougi M (2015) PD-L1 expression in renal cell carcinoma clear cell type is related to unfavorable prognosis. Diagn Pathol 10:189. https://doi.org/10.1186/s13000-015-0414-xCrossRefPubMedPubMedCentral

13.

Shin SJ, Jeon YK, Kim PJ, Cho YM, Koh J, Chung DH, Go H (2016) Clinicopathologic analysis of PD-L1 and PD-L2 expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol 23:694–702. https://doi.org/10.1245/s10434-015-4903-7CrossRefPubMed

14.

Iacovelli R, Nole F, Verri E et al (2016) Prognostic role of PD-L1 expression in renal cell carcinoma. a systematic review and meta-analysis. Target Oncol 11:143–148. https://doi.org/10.1007/s11523-015-0392-7CrossRefPubMed

15.

Kim SH, Park WS, Park EY, Park B, Joo J, Joung JY, Seo HK, Lee KH, Chung J (2017) The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue markers in localized renal cell carcinoma: a retrospective study of tissue microarrays using immunohistochemistry. PLoS ONE 12:e0179610. https://doi.org/10.1371/journal.pone.0179610CrossRefPubMedPubMedCentral

16.

Simon I, Zhuo S, Corral L, Diamandis EP, Sarno MJ, Wolfert RL, Kim NW (2006) B7-H4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer. Cancer Res 66:1570–1575. https://doi.org/10.1158/0008-5472.CAN-04-3550CrossRefPubMed

17.

Krambeck AE, Thompson RH, Dong H et al (2006) B7–H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Proc Natl Acad Sci USA 103:10391–10396. https://doi.org/10.1073/pnas.0600937103CrossRefPubMedPubMedCentral

18.

Shen L, Qian Y, Wu W et al (2017) B7-H4 is a prognostic biomarker for poor survival in patients with pancreatic cancer. Hum Pathol 66:79–85. https://doi.org/10.1016/j.humpath.2017.05.023CrossRefPubMed

19.

Thijssen VL, Heusschen R, Caers J, Griffioen AW (2015) Galectin expression in cancer diagnosis and prognosis: a systematic review. Biochim Biophys Acta 1855:235–247. https://doi.org/10.1016/j.bbcan.2015.03.003CrossRefPubMed

20.

Mok TSK, Wu YL, Kudaba I et al (2019) Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 393:1819–1830. https://doi.org/10.1016/S0140-6736(18)32409-7CrossRefPubMed

21.

Yeong J, Zhao Z, Lim JCT et al (2020) PD-L1 expression is an unfavourable prognostic indicator in Asian renal cell carcinomas. J Clin Pathol. https://doi.org/10.1136/jclinpath-2019-206092CrossRefPubMed

22.

Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transpl 48:452–458. https://doi.org/10.1038/bmt.2012.244CrossRef

23.

Kageshita T, Kashio Y, Yamauchi A et al (2002) Possible role of galectin-9 in cell aggregation and apoptosis of human melanoma cell lines and its clinical significance. Int J Cancer 99:809–816. https://doi.org/10.1002/ijc.10436CrossRefPubMed

24.

Irie A, Yamauchi A, Kontani K et al (2005) Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer. Clin Cancer Res 11:2962–2968. https://doi.org/10.1158/1078-0432.CCR-04-0861CrossRefPubMed

25.

Liang M, Ueno M, Oomizu S, Arikawa T, Shinonaga R, Zhang S, Yamauchi A, Hirashima M (2008) Galectin-9 expression links to malignant potential of cervical squamous cell carcinoma. J Cancer Res Clin Oncol 134:899–907. https://doi.org/10.1007/s00432-008-0352-zCrossRefPubMed

26.

Zhang ZY, Dong JH, Chen YW, Wang XQ, Li CH, Wang J, Wang GQ, Li HL, Wang XD (2012) Galectin-9 acts as a prognostic factor with antimetastatic potential in hepatocellular carcinoma. Asian Pac J Cancer Prev 13:2503–2509. https://doi.org/10.7314/apjcp.2012.13.6.2503CrossRefPubMed

27.

Fu H, Liu Y, Xu L, Liu W, Fu Q, Liu H, Zhang W, Xu J (2015) Galectin-9 predicts postoperative recurrence and survival of patients with clear-cell renal cell carcinoma. Tumour Biol 36:5791–5799. https://doi.org/10.1007/s13277-015-3248-yCrossRefPubMed

28.

Qi Y, Chang Y, Wang Z et al (2019) Tumor-associated macrophages expressing galectin-9 identify immunoevasive subtype muscle-invasive bladder cancer with poor prognosis but favorable adjuvant chemotherapeutic response. Cancer Immunol Immunother 68:2067–2080. https://doi.org/10.1007/s00262-019-02429-2CrossRefPubMed

29.

Li H, Wu K, Tao K et al (2012) Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56:1342–1351. https://doi.org/10.1002/hep.25777CrossRefPubMed

30.

Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6:1245–1252. https://doi.org/10.1038/ni1271CrossRefPubMed

31.

Granier C, Dariane C, Combe P et al (2017) Tim-3 expression on tumor-infiltrating PD-1⁽⁺⁾CD⁸⁽⁺⁾ T cells correlates with poor clinical outcome in renal cell carcinoma. Cancer Res 77:1075–1082. https://doi.org/10.1158/0008-5472.CAN-16-0274CrossRefPubMed

32.

Podojil JR, Miller SD (2017) Potential targeting of B7-H4 for the treatment of cancer. Immunol Rev 276:40–51. https://doi.org/10.1111/imr.12530CrossRefPubMedPubMedCentral

33.

Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895CrossRefPubMedPubMedCentral

34.

Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687. https://doi.org/10.1038/nature04444CrossRefPubMed

35.

Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8:467–477. https://doi.org/10.1038/nri2326CrossRefPubMed

36.

Ohigashi Y, Sho M, Yamada Y et al (2005) Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 11:2947–2953. https://doi.org/10.1158/1078-0432.CCR-04-1469CrossRefPubMed

37.

Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N (2006) Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 108:19–24. https://doi.org/10.1016/j.acthis.2006.01.003CrossRefPubMed

38.

Hamanishi J, Mandai M, Iwasaki M et al (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD⁸⁺ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104:3360–3365. https://doi.org/10.1073/pnas.0611533104CrossRefPubMedPubMedCentral

39.

Droeser RA, Hirt C, Viehl CT et al (2013) Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 49:2233–2242. https://doi.org/10.1016/j.ejca.2013.02.015CrossRefPubMed

40.

Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, Rimm DL (2014) In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res 20:2773–2782. https://doi.org/10.1158/1078-0432.CCR-13-2702CrossRefPubMed

41.

Lipson EJ, Vincent JG, Loyo M et al (2013) PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res 1:54–63. https://doi.org/10.1158/2326-6066.CIR-13-0034CrossRefPubMed

42.

Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287. https://doi.org/10.1038/nrc.2016.36CrossRefPubMedPubMedCentral

43.

Bu M, Shen Y, Seeger WL, An S, Qi R, Sanderson JA, Cai Y (2016) Ovarian carcinoma-infiltrating regulatory T cells were more potent suppressors of CD⁸⁽⁺⁾ T cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression. Tumour Biol 37:3949–3956. https://doi.org/10.1007/s13277-015-4237-xCrossRefPubMed

44.

Liu Z, McMichael EL, Shayan G, Li J, Chen K, Srivastava R, Kane LP, Lu B, Ferris RL (2018) Novel effector phenotype of Tim-3(+) regulatory T cells leads to enhanced suppressive function in head and neck cancer patients. Clin Cancer Res 24:4529–4538. https://doi.org/10.1158/1078-0432.CCR-17-1350CrossRefPubMedPubMedCentral

45.

Liu JF, Wu L, Yang LL, Deng WW, Mao L, Wu H, Zhang WF, Sun ZJ (2018) Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer. J Exp Clin Cancer Res 37:44. https://doi.org/10.1186/s13046-018-0713-7CrossRefPubMedPubMedCentral

Title: Galectin-9 expression as a poor prognostic factor in patients with renal cell carcinoma
Authors: Ryosuke Jikuya
Takeshi Kishida
Masahiko Sakaguchi
Tomoyuki Yokose
Masato Yasui
Akihito Hashizume
Tomoyuki Tatenuma
Nobuhiko Mizuno
Kentaro Muraoka
Susumu Umemoto
Masaki Kawai
Mitsuyo Yoshihara
Yoshiyasu Nakamura
Yohei Miyagi
Tetsuro Sasada
Publication date: 01-10-2020
Publisher: Springer Berlin Heidelberg
Keywords: Kidney Cancer
Kidney Cancer
Kidney Cancer
Published in: Cancer Immunology, Immunotherapy / Issue 10/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02608-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 10/2020

Activated HIF1α of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer

Prevention of liver metastases through perioperative acute CpG-C immune stimulation

Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer

Successful treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis with triple combination therapy: a case report

Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy

Observations on neuroimmunomodulation as a novel therapeutic strategy in metastasis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer