Top

Published in:

Open Access 01-03-2021 | osteosarcoma | Clinical

Galectin-3: an immune checkpoint target for musculoskeletal tumor patients

Authors: Kosei Nakajima, Vitaly Balan, Avraham Raz

Published in: Cancer and Metastasis Reviews | Issue 1/2021

Abstract

In the past decade, the development of immune checkpoint inhibitors in oncological clinical settings was in the forefront. However, the interest in musculoskeletal tumor patients as candidates for checkpoint inhibition remains underserved. Here, we are forwarding evidence proposing that galectin-3 (Gal-3) is an additional immune factor in the checkpoint processes. This review is the result of a large-scale cohort study depicting that overexpression of Gal-3 was widely prevalent in patients with musculoskeletal tumors, whereas T cell infiltrations were generally suppressed in the tumor microenvironment. Targeting Gal-3 would serve as a novel immune checkpoint inhibitor candidate in patients afflicted with aggressive musculoskeletal tumors.

Raz, A., Bucana, C., McLellan, W., & Fidler, I. J. (1980). Distribution of membrane anionic sites on B16 melanoma variants with differing lung colonising potential. Nature, 284(5754), 363–364. https://doi.org/10.1038/284363a0.CrossRefPubMed

Raz, A., & Lotan, R. (1981). Lectin-like activities associated with human and murine neoplastic cells. Cancer Research, 41(9 Pt 1), 3642–3647.PubMed

Inohara, H., & Raz, A. (1994). Identification of human melanoma cellular and secreted ligands for galectin-3. Biochemical and Biophysical Research Communications, 201(3), 1366–1375. https://doi.org/10.1006/bbrc.1994.1854.CrossRefPubMed

Nakajima, K., Kho, D. H., Yanagawa, T., Zimel, M., Heath, E., Hogan, V., & Raz, A. (2016). Galectin-3 in bone tumor microenvironment: a beacon for individual skeletal metastasis management. Cancer Metastasis Reviews, 35(2), 333–346. https://doi.org/10.1007/s10555-016-9622-4.CrossRefPubMedPubMedCentral

Nakajima, K., & Raz, A. (in submission). Galectin-3 expressional profile in musculoskeletal tumor patients.

Zhou, X., Jing, J., Peng, J., Mao, W., Zheng, Y., Wang, D., Wang, X., Liu, Z., & Zhang, X. (2014). Expression and clinical significance of galectin-3 in osteosarcoma. Gene, 546(2), 403–407. https://doi.org/10.1016/j.gene.2014.04.066.CrossRefPubMed

Park, G. B., Kim, D. J., Kim, Y. S., Lee, H. K., Kim, C. W., & Hur, D. Y. (2015). Silencing of galectin-3 represses osteosarcoma cell migration and invasion through inhibition of FAK/Src/Lyn activation and β-catenin expression and increases susceptibility to chemotherapeutic agents. International Journal of Oncology, 46(1), 185–194. https://doi.org/10.3892/ijo.2014.2721.CrossRefPubMed

Lei, P., He, H., Hu, Y., & Liao, Z. (2015). Small interfering RNA-induced silencing of galectin-3 inhibits the malignant phenotypes of osteosarcoma in vitro. Molecular Medicine Reports, 12(4), 6316–6322. https://doi.org/10.3892/mmr.2015.4165.CrossRefPubMed

Mercer, N., Ahmed, H., McCarthy, A. D., Etcheverry, S. B., Vasta, G. R., & Cortizo, A. M. (2004). AGE-R3/galectin-3 expression in osteoblast-like cells: regulation by AGEs. Molecular and Cellular Biochemistry, 266(1–2), 17–24. https://doi.org/10.1023/b:mcbi.0000049128.71095.ac.CrossRefPubMed

10.

Nakajima, K., Kho, D. H., Yanagawa, T., Harazono, Y., Gao, X., Hogan, V., & Raz, A. (2014). Galectin-3 inhibits osteoblast differentiation through notch signaling. Neoplasia, 16(11), 939–949. https://doi.org/10.1016/j.neo.2014.09.005.CrossRefPubMedPubMedCentral

11.

Nakajima, K., Kho, D. H., Yanagawa, T., Harazono, Y., Hogan, V., Chen, W., Ali-Fehmi, R., Mehra, R., & Raz, A. (2016). Galectin-3 cleavage alters bone remodeling: different outcomes in breast and prostate cancer skeletal metastasis. Cancer Research, 76(6), 1391–1402. https://doi.org/10.1158/0008-5472.Can-15-1793.CrossRefPubMedPubMedCentral

12.

Lehr, J. E., & Pienta, K. J. (1998). Preferential adhesion of prostate cancer cells to a human bone marrow endothelial cell line. Journal of the National Cancer Institute, 90(2), 118–123. https://doi.org/10.1093/jnci/90.2.118.CrossRefPubMed

13.

Glinskii, O. V., Huxley, V. H., Glinsky, G. V., Pienta, K. J., Raz, A., & Glinsky, V. V. (2005). Mechanical entrapment is insufficient and intercellular adhesion is essential for metastatic cell arrest in distant organs. Neoplasia, 7(5), 522–527. https://doi.org/10.1593/neo.04646.CrossRefPubMedPubMedCentral

14.

Glinskii, O. V., Sud, S., Mossine, V. V., Mawhinney, T. P., Anthony, D. C., Glinsky, G. V., Pienta, K. J., & Glinsky, V. V. (2012). Inhibition of prostate cancer bone metastasis by synthetic TF antigen mimic/galectin-3 inhibitor lactulose-L-leucine. Neoplasia, 14(1), 65–73. https://doi.org/10.1593/neo.111544.CrossRefPubMedPubMedCentral

15.

Crompton, B. D., Stewart, C., Taylor-Weiner, A., Alexe, G., Kurek, K. C., Calicchio, M. L., Kiezun, A., Carter, S. L., Shukla, S. A., Mehta, S. S., Thorner, A. R., de Torres, C., Lavarino, C., Sunol, M., McKenna, A., Sivachenko, A., Cibulskis, K., Lawrence, M. S., Stojanov, P., Rosenberg, M., Ambrogio, L., Auclair, D., Seepo, S., Blumenstiel, B., DeFelice, M., Imaz-Rosshandler, I., Schwarz-Cruz y Celis, A., Rivera, M. N., Rodriguez-Galindo, C., Fleming, M. D., Golub, T. R., Getz, G., Mora, J., & Stegmaier, K. (2014). The genomic landscape of pediatric Ewing sarcoma. Cancer Discovery, 4(11), 1326–1341. https://doi.org/10.1158/2159-8290.Cd-13-1037.CrossRefPubMed

16.

De Feo, A., Sciandra, M., Ferracin, M., Felicetti, F., Astolfi, A., Pignochino, Y., et al. (2019). Exosomes from CD99-deprived Ewing sarcoma cells reverse tumor malignancy by inhibiting cell migration and promoting neural differentiation. Cell Death & Disease, 10(7), 471. https://doi.org/10.1038/s41419-019-1675-1.CrossRef

17.

Zambelli, D., Zuntini, M., Nardi, F., Manara, M. C., Serra, M., Landuzzi, L., Lollini, P. L., Ferrari, S., Alberghini, M., Llombart-Bosch, A., Piccolo, E., Iacobelli, S., Picci, P., & Scotlandi, K. (2010). Biological indicators of prognosis in Ewing's sarcoma: an emerging role for lectin galactoside-binding soluble 3 binding protein (LGALS3BP). International Journal of Cancer, 126(1), 41–52. https://doi.org/10.1002/ijc.24670.CrossRefPubMed

18.

Juliao, S. F., Rand, N., & Schwartz, H. S. (2002). Galectin-3: a biologic marker and diagnostic aid for chordoma. Clin Orthop Relat Res, (397), 70–75. https://doi.org/10.1097/00003086-200204000-00010.

19.

Shen, J., Li, C. D., Yang, H. L., Lu, J., Zou, T. M., Wang, D. L., & Deng, M. (2011). Classic chordoma coexisting with benign notochordal cell rest demonstrating different immunohistological expression patterns of brachyury and galectin-3. Journal of Clinical Neuroscience, 18(1), 96–99. https://doi.org/10.1016/j.jocn.2010.03.066.CrossRefPubMed

20.

Bigotti, G., Coli, A., Del Vecchio, M., & Massi, G. (2003). Evaluation of galectin-3 expression by sarcomas, pseudosarcomatous and benign lesions of the soft tissues. Preliminary results of an immunohistochemical study. Journal of Experimental & Clinical Cancer Research, 22(2), 255–264.

21.

Weissenbacher, T., Kuhn, C., Mayr, D., Pavlik, R., Friese, K., Scholz, C., Jeschke, U., Ditsch, N., & Dian, D. (2011). Expression of mucin-1, galectin-1 and galectin-3 in human leiomyosarcoma in comparison to leiomyoma and myometrium. Anticancer Research, 31(2), 451–457.PubMed

22.

Johnson, K. D., Glinskii, O. V., Mossine, V. V., Turk, J. R., Mawhinney, T. P., Anthony, D. C., Henry, C. J., Huxley, V. H., Glinsky, G. V., Pienta, K. J., Raz, A., & Glinsky, V. V. (2007). Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia. Neoplasia, 9(8), 662–670. https://doi.org/10.1593/neo.07433.CrossRefPubMedPubMedCentral

23.

Ayodele, O., & Razak, A. R. A. (2020). Immunotherapy in soft-tissue sarcoma. Current Oncology, 27(Suppl 1), 17–23. https://doi.org/10.3747/co.27.5407.CrossRefPubMedPubMedCentral

24.

Wedekind, M. F., Wagner, L. M., & Cripe, T. P. (2018). Immunotherapy for osteosarcoma: where do we go from here? Pediatric Blood & Cancer, 65(9), e27227. https://doi.org/10.1002/pbc.27227.CrossRef

25.

Landi, L., D'Incà, F., Gelibter, A., Chiari, R., Grossi, F., Delmonte, A., et al. (2019). Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer. Journal for Immunotherapy of Cancer, 7(1), 316. https://doi.org/10.1186/s40425-019-0793-8.CrossRefPubMedPubMedCentral

26.

Thanindratarn, P., Dean, D. C., Nelson, S. D., Hornicek, F. J., & Duan, Z. (2020). Chimeric antigen receptor T (CAR-T) cell immunotherapy for sarcomas: From mechanisms to potential clinical applications. Cancer Treatment Reviews, 82, 101934. https://doi.org/10.1016/j.ctrv.2019.101934.CrossRefPubMed

27.

D'Angelo, S. P., Melchiori, L., Merchant, M. S., Bernstein, D., Glod, J., Kaplan, R., Grupp, S., Tap, W. D., Chagin, K., Binder, G. K., Basu, S., Lowther, D. E., Wang, R., Bath, N., Tipping, A., Betts, G., Ramachandran, I., Navenot, J. M., Zhang, H., Wells, D. K., van Winkle, E., Kari, G., Trivedi, T., Holdich, T., Pandite, L., Amado, R., & Mackall, C. L. (2018). Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 (c259)T cells in synovial sarcoma. Cancer Discovery, 8(8), 944–957. https://doi.org/10.1158/2159-8290.Cd-17-1417.CrossRefPubMed

28.

George, S. (2019). Developments in systemic therapy for soft tissue and bone sarcomas. J Natl Compr Canc Netw, 17(5.5), 625–628. https://doi.org/10.6004/jnccn.2019.5020.CrossRefPubMed

29.

Nakajima, K., Nangia-Makker, P., Hogan, V., & Raz, A. (2017). Cancer self-defense: an immune stealth. Cancer Research, 77(20), 5441–5444. https://doi.org/10.1158/0008-5472.Can-17-1324.CrossRefPubMedPubMedCentral

30.

Fukumori, T., Takenaka, Y., Yoshii, T., Kim, H. R., Hogan, V., Inohara, H., Kagawa, S., & Raz, A. (2003). CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. Cancer Research, 63(23), 8302–8311.PubMed

31.

Stillman, B. N., Hsu, D. K., Pang, M., Brewer, C. F., Johnson, P., Liu, F. T., & Baum, L. G. (2006). Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. Journal of Immunology, 176(2), 778–789. https://doi.org/10.4049/jimmunol.176.2.778.CrossRef

32.

Chen, H. Y., Fermin, A., Vardhana, S., Weng, I. C., Lo, K. F., Chang, E. Y., et al. (2009). Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse. Proceedings of the National Academy of Sciences of the United States of America, 106(34), 14496–14501. https://doi.org/10.1073/pnas.0903497106.CrossRefPubMedPubMedCentral

33.

Kouo, T., Huang, L., Pucsek, A. B., Cao, M., Solt, S., Armstrong, T., & Jaffee, E. (2015). Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunology Research, 3(4), 412–423. https://doi.org/10.1158/2326-6066.Cir-14-0150.CrossRefPubMedPubMedCentral

34.

He, Y., Rivard, C. J., Rozeboom, L., Yu, H., Ellison, K., Kowalewski, A., Zhou, C., & Hirsch, F. R. (2016). Lymphocyte-activation gene-3, an important immune checkpoint in cancer. Cancer Science, 107(9), 1193–1197. https://doi.org/10.1111/cas.12986.CrossRefPubMedPubMedCentral

35.

Andrews, L. P., Marciscano, A. E., Drake, C. G., & Vignali, D. A. (2017). LAG3 (CD223) as a cancer immunotherapy target. Immunological Reviews, 276(1), 80–96. https://doi.org/10.1111/imr.12519.CrossRefPubMedPubMedCentral

36.

Triebel, F., Jitsukawa, S., Baixeras, E., Roman-Roman, S., Genevee, C., Viegas-Pequignot, E., & Hercend, T. (1990). LAG-3, a novel lymphocyte activation gene closely related to CD4. The Journal of Experimental Medicine, 171(5), 1393–1405. https://doi.org/10.1084/jem.171.5.1393.CrossRefPubMed

37.

Xu, F., Liu, J., Liu, D., Liu, B., Wang, M., Hu, Z., du, X., Tang, L., & He, F. (2014). LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Research, 74(13), 3418–3428. https://doi.org/10.1158/0008-5472.Can-13-2690.CrossRefPubMed

38.

Nakajima, K., & Raz, A. (in submission). T cell infiltration profile in musculoskeletal tumors.

39.

Nakajima, K., Heilbrun, L. K., Hogan, V., Smith, D., Heath, E., & Raz, A. (2016). Positive associations between galectin-3 and PSA levels in prostate cancer patients: a prospective clinical study-I. Oncotarget, 7(50), 82266–82272. https://doi.org/10.18632/oncotarget.12619.CrossRefPubMedPubMedCentral

40.

Nangia-Makker, P., Hogan, V., Honjo, Y., Baccarini, S., Tait, L., Bresalier, R., & Raz, A. (2002). Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. Journal of the National Cancer Institute, 94(24), 1854–1862. https://doi.org/10.1093/jnci/94.24.1854.CrossRefPubMed

41.

Chalasani, N., Abdelmalek, M. F., Garcia-Tsao, G., Vuppalanchi, R., Alkhouri, N., Rinella, M., et al. (2020). Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology, 158(5), 1334-1345.e1335. https://doi.org/10.1053/j.gastro.2019.11.296.CrossRef

42.

Harrison, S. A., Marri, S. R., Chalasani, N., Kohli, R., Aronstein, W., Thompson, G. A., Irish, W., Miles, M. V., Xanthakos, S. A., Lawitz, E., Noureddin, M., Schiano, T. D., Siddiqui, M., Sanyal, A., Neuschwander-Tetri, B. A., & Traber, P. G. (2016). Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Alimentary Pharmacology & Therapeutics, 44(11–12), 1183–1198. https://doi.org/10.1111/apt.13816.CrossRef

43.

Ritchie, S., Neal, D., Shlevin, H., Allgood, A., & Traber, P. (2017). A phase 2a, open-label pilot study of the galectin-3 inhibitor GR-MD-02 for the treatment of moderate-to-severe plaque psoriasis. Journal of the American Academy of Dermatology, 77(4), 753–755. https://doi.org/10.1016/j.jaad.2017.05.055.CrossRefPubMed

44.

Galectin inhibitor (GR-MD-02) and ipilimumab in patients with metastatic melanoma. ClinicalTrials.govIdentifier: NCT02117362.

45.

Cotter, F., Smith, D., Boyd, T., Richards, T., Alemany, C., Loeschg, D., et al. (2009). Single-agent activity of GCS-100, a first-in-class galectin-3 antagonist, in elderly patients with relapsed chronic lymphocytic leukemia. J Clin Oncol, 27(15) (suppl), 7006.CrossRef

46.

Grous, J., Redfern, C., Mahadevan, D., & Schindler, J. (2006). GCS-100, a galectin-3 antagonist, in refractory solid tumors: a phase I study. J Clin Oncol, 24(18) (Suppl), 13023.CrossRef

47.

Keizman, D., Frenkel, M., Peer, A., Rosenbaum, E., Margel, D., Sarid, D., et al. (2019). Effect of pectasol-c modified citrus pectin (P-MCP) treatment on PSA dynamics in non- metastatic biochemically relapsed prostate cancer patients: primary outcome analysis of a prospective phase II study. J Clin Oncol, 37(15) (suppl), e16609.CrossRef

48.

Seetharaman, J., Kanigsberg, A., Slaaby, R., Leffler, H., Barondes, S. H., & Rini, J. M. (1998). X-ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2.1-a resolution. The Journal of Biological Chemistry, 273(21), 13047–13052. https://doi.org/10.1074/jbc.273.21.13047.CrossRefPubMed

49.

Mathews, K. P., Konstantinov, K. N., Kuwabara, I., Hill, P. N., Hsu, D. K., Zuraw, B. L., & Liu, F. T. (1995). Evidence for IgG autoantibodies to galectin-3, a beta-galactoside-binding lectin (Mac-2, epsilon binding protein, or carbohydrate binding protein 35) in human serum. Journal of Clinical Immunology, 15(6), 329–337. https://doi.org/10.1007/bf01541323.CrossRefPubMed

50.

Rotte, A., Jin, J. Y., & Lemaire, V. (2018). Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Annals of Oncology, 29(1), 71–83. https://doi.org/10.1093/annonc/mdx686.CrossRefPubMed

Title: Galectin-3: an immune checkpoint target for musculoskeletal tumor patients
Authors: Kosei Nakajima
Vitaly Balan
Avraham Raz
Publication date: 01-03-2021
Publisher: Springer US
Keywords: osteosarcoma
Ewing's Sarcoma
Ewing's sarcoma
Soft Tissue Sarcoma
Osteosarcoma
Checkpoint Inhibitors
Published in: Cancer and Metastasis Reviews / Issue 1/2021
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-020-09932-4

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 1/2021

An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression

Neutrophil-derived granule cargoes: paving the way for tumor growth and progression

Visualizing cancer extravasation: from mechanistic studies to drug development

Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis

Macrophages in multiple myeloma: key roles and therapeutic strategies

Targeting the cytoskeleton against metastatic dissemination

Keynote webinar | Spotlight on antibody–drug conjugates in cancer