Top

Published in:

01-12-2020 | Breast Cancer | Original Article

TIM-3 blockade combined with bispecific antibody MT110 enhances the anti-tumor effect of γδ T cells

Published in: Cancer Immunology, Immunotherapy | Issue 12/2020

Abstract

As ideal cells that can be used for adoptive cell therapy, γδ T cells are a group of homogeneous cells with high proliferative and tumor killing ability. However, γδ T cells are apt to apoptosis and show decreased cytotoxicity under persistent stimulation in vitro and cannot aggregate at tumor sites efficiently in vivo, both of which are two main obstacles to tumor adoptive immunotherapy. In this study, we found that the immune checkpoint T-cell immunoglobulin domain and mucin domain 3 (TIM-3) were up-regulated significantly on γδ T cells during their ex vivo expansion and this up-regulation contributed to the dysfunction of γδ T cells. Although the killing ability of γδ T cells against breast cancer cells which exhibited a high level of epithelial cell adhesion molecule (EpCAM) was enhanced, the level of TIM-3 on γδ T cells was also further up-regulated under the application of the bispecific antibody MT110 (anti-CD3 × anti-EpCAM) which can redirect T cells to target cells. Besides, these γδ T cells with up-regulated TIM-3 exhibited an increased susceptibility to apoptosis. By reinvigorating dysfunctional γδ T cells and promoting them to accumulate at tumor sites, the combined use of TIM-3 inhibitor and MT110 could further enhance the anti-tumor effect of the adoptively transfused γδ T cells. These results may have clinical implications for the design of new translational anti-tumor regimens aimed at combining checkpoint blockade and immune cell redirection.

Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111. https://doi.org/10.1038/35074122CrossRefPubMed

Bielamowicz K, Khawja S, Ahmed N (2013) Adoptive cell therapies for glioblastoma. Front Oncol 3:275. https://doi.org/10.3389/fonc.2013.00275CrossRefPubMedPubMedCentral

Pennington DJ, Silva-Santos B, Hayday AC (2005) Gammadelta T cell development—having the strength to get there. Curr Opin Immunol 17:108–115. https://doi.org/10.1016/j.coi.2005.01.009CrossRefPubMed

Bonneville M, Scotet E (2006) Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors. Curr Opin Immunol 18:539–546. https://doi.org/10.1016/j.coi.2006.07.002CrossRefPubMed

Das H, Wang L, Kamath A, Bukowski JF (2001) Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates. Blood 98:1616–1618CrossRefPubMed

Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G (2003) Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197:163–168. https://doi.org/10.1084/jem.20021500CrossRefPubMedPubMedCentral

Bouet-Toussaint F, Cabillic F, Toutirais O et al (2008) Vgamma9Vdelta2 T cell-mediated recognition of human solid tumors. Potential for immunotherapy of hepatocellular and colorectal carcinomas. Cancer Immunol Immunother 57:531–539. https://doi.org/10.1007/s00262-007-0391-3CrossRefPubMed

Yi JS, Cox MA, Zajac AJ (2010) T-cell exhaustion: characteristics, causes and conversion. Immunology 129:474–481. https://doi.org/10.1111/j.1365-2567.2010.03255.xCrossRefPubMedPubMedCentral

Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. https://doi.org/10.1038/nrc3239CrossRefPubMedPubMedCentral

10.

Marin-Acevedo JA, Dholaria B, Soyano AE, Knutson KL, Chumsri S, Lou Y (2018) Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol 11:39. https://doi.org/10.1186/s13045-018-0582-8CrossRefPubMedPubMedCentral

11.

Shin DS, Ribas A (2015) The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? Curr Opin Immunol 33:23–35. https://doi.org/10.1016/j.coi.2015.01.006CrossRefPubMed

12.

Monney L, Sabatos CA, Gaglia JL et al (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415:536–541. https://doi.org/10.1038/415536aCrossRefPubMed

13.

Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207:2187–2194. https://doi.org/10.1084/jem.20100643CrossRefPubMedPubMedCentral

14.

Gorman JV, Starbeck-Miller G, Pham NL, Traver GL, Rothman PB, Harty JT, Colgan JD (2014) Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection. J Immunol 192:3133–3142. https://doi.org/10.4049/jimmunol.1302290CrossRefPubMed

15.

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

16.

Burges A, Wimberger P, Kumper C et al (2007) Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a phase I/II study. Clin Cancer Res 13:3899–3905. https://doi.org/10.1158/1078-0432.CCR-06-2769CrossRefPubMed

17.

Jager M, Schoberth A, Ruf P et al (2012) Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3). Cancer Res 72:24–32. https://doi.org/10.1158/0008-5472.CAN-11-2235CrossRefPubMed

18.

Dreier T, Lorenczewski G, Brandl C et al (2002) Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. Int J Cancer 100:690–697. https://doi.org/10.1002/ijc.10557CrossRefPubMed

19.

Wada J, Ota K, Kumar A, Wallner EI, Kanwar YS (1997) Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest 99:2452–2461. https://doi.org/10.1172/JCI119429CrossRefPubMedPubMedCentral

20.

Heusschen R, Griffioen AW, Thijssen VL (2013) Galectin-9 in tumor biology: a jack of multiple trades. Biochim Biophys Acta 1836:177–185. https://doi.org/10.1016/j.bbcan.2013.04.006CrossRefPubMed

21.

Lipson EJ, Sharfman WH, Drake CG et al (2013) Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19:462–468. https://doi.org/10.1158/1078-0432.CCR-12-2625CrossRefPubMed

22.

Calabro L, Morra A, Fonsatti E et al (2013) Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 14:1104–1111. https://doi.org/10.1016/S1470-2045(13)70381-4CrossRefPubMed

23.

Todaro M, D’Asaro M, Caccamo N et al (2009) Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes. J Immunol 182:7287–7296. https://doi.org/10.4049/jimmunol.0804288CrossRefPubMed

24.

Dhar S, Chiplunkar SV (2010) Lysis of aminobisphosphonate-sensitized MCF-7 breast tumor cells by Vgamma9Vdelta2 T cells. Cancer Immun 10:10PubMedPubMedCentral

25.

Ishiguro T, Sano Y, Komatsu SI et al (2017) An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aal4291CrossRefPubMed

26.

Brischwein K, Schlereth B, Guller B et al (2006) MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors. Mol Immunol 43:1129–1143. https://doi.org/10.1016/j.molimm.2005.07.034CrossRefPubMed

27.

Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, Dirnhofer S (2004) Frequent EpCam protein expression in human carcinomas. Hum Pathol 35:122–128CrossRefPubMed

28.

Zheng Y, Li Y, Lian J, Yang H, Li F, Zhao S, Qi Y, Zhang Y, Huang L (2019) TNF-α-induced Tim-3 expression marks the dysfunction of infiltrating natural killer cells in human esophageal cancer. J Transl Med. https://doi.org/10.1186/s12967-019-1917-0CrossRefPubMedPubMedCentral

29.

Kobayashi H, Tanaka Y, Shimmura H, Minato N, Tanabe K (2010) Complete remission of lung metastasis following adoptive immunotherapy using activated autologous gammadelta T-cells in a patient with renal cell carcinoma. Anticancer Res 30:575–579PubMed

30.

Abe Y, Muto M, Nieda M, Nakagawa Y, Nicol A, Kaneko T, Goto S, Yokokawa K, Suzuki K (2009) Clinical and immunological evaluation of zoledronate-activated Vgamma9gammadelta T-cell-based immunotherapy for patients with multiple myeloma. Exp Hematol 37:956–968. https://doi.org/10.1016/j.exphem.2009.04.008CrossRefPubMed

31.

Ensslin AS, Formby B (1991) Comparison of cytolytic and proliferative activities of human gamma delta and alpha beta T cells from peripheral blood against various human tumor cell lines. J Natl Cancer Inst 83:1564–1569. https://doi.org/10.1093/jnci/83.21.1564CrossRefPubMed

32.

Chung MJ, Park JY, Bang S, Park SW, Song SY (2014) Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer. Cancer Immunol Immunother 63:939–946. https://doi.org/10.1007/s00262-014-1566-3CrossRefPubMed

33.

Klingemann H (2015) Challenges of cancer therapy with natural killer cells. Cytotherapy 17:245–249. https://doi.org/10.1016/j.jcyt.2014.09.007CrossRefPubMed

34.

Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM (2010) Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8 + T cell dysfunction in melanoma patients. J Exp Med 207:2175–2186. https://doi.org/10.1084/jem.20100637CrossRefPubMedPubMedCentral

35.

Iwasaki M, Tanaka Y, Kobayashi H, Murata-Hirai K, Miyabe H, Sugie T, Toi M, Minato N (2011) Expression and function of PD-1 in human gammadelta T cells that recognize phosphoantigens. Eur J Immunol 41:345–355. https://doi.org/10.1002/eji.201040959CrossRefPubMed

36.

Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, Freeman GJ, Kuchroo VK, Ahmed R (2010) Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA 107:14733–14738. https://doi.org/10.1073/pnas.1009731107CrossRefPubMedPubMedCentral

37.

Tureci O, Schmitt H, Fadle N, Pfreundschuh M, Sahin U (1997) Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin’s disease. J Biol Chem 272:6416–6422. https://doi.org/10.1074/jbc.272.10.6416CrossRefPubMed

38.

Lahm H, Andre S, Hoeflich A, Fischer JR, Sordat B, Kaltner H, Wolf E, Gabius HJ (2001) Comprehensive galectin fingerprinting in a panel of 61 human tumor cell lines by RT-PCR and its implications for diagnostic and therapeutic procedures. J Cancer Res Clin Oncol 127:375–386CrossRefPubMed

39.

Chabot S, Kashio Y, Seki M, Shirato Y, Nakamura K, Nishi N, Nakamura T, Matsumoto R, Hirashima M (2002) Regulation of galectin-9 expression and release in Jurkat T cell line cells. Glycobiology 12:111–118. https://doi.org/10.1093/glycob/12.2.111CrossRefPubMed

40.

Rabinovich GA, Rubinstein N, Toscano MA (2002) Role of galectins in inflammatory and immunomodulatory processes. Biochim Biophys Acta 1572:274–284CrossRefPubMed

41.

Wang F, He W, Zhou H, Yuan J, Wu K, Xu L, Chen ZK (2007) The Tim-3 ligand galectin-9 negatively regulates CD8 + alloreactive T cell and prolongs survival of skin graft. Cell Immunol 250:68–74. https://doi.org/10.1016/j.cellimm.2008.01.006CrossRefPubMed

42.

Wang F, He W, Yuan J, Wu K, Zhou H, Zhang W, Chen ZK (2008) Activation of Tim-3-Galectin-9 pathway improves survival of fully allogeneic skin grafts. Transpl Immunol 19:12–19. https://doi.org/10.1016/j.trim.2008.01.008CrossRefPubMed

43.

Brischwein K, Parr L, Pflanz S et al (2007) Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. J Immunother 30:798–807. https://doi.org/10.1097/CJI.0b013e318156750cCrossRefPubMed

44.

Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174. https://doi.org/10.1038/nri2506CrossRefPubMedPubMedCentral

45.

Whiteside TL, Schuler P, Schilling B (2012) Induced and natural regulatory T cells in human cancer. Expert Opin Biol Ther 12:1383–1397. https://doi.org/10.1517/14712598.2012.707184CrossRefPubMedPubMedCentral

46.

Obeid E, Nanda R, Fu YX, Olopade OI (2013) The role of tumor-associated macrophages in breast cancer progression (review). Int J Oncol 43:5–12. https://doi.org/10.3892/ijo.2013.1938CrossRefPubMedPubMedCentral

Title: TIM-3 blockade combined with bispecific antibody MT110 enhances the anti-tumor effect of γδ T cells
Publication date: 01-12-2020
Keywords: Breast Cancer
Breast Cancer
Published in: Cancer Immunology, Immunotherapy / Issue 12/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02638-0

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 12/2020

Factors associated with ocular adverse event after immune checkpoint inhibitor treatment

Characterizing caspase-1 involvement during esophageal disease progression

Pretreatment body mass index and clinical outcomes in cancer patients following immune checkpoint inhibitors: a systematic review and meta-analysis

Carrying the torch & facing new challenges

The adjuvant effect of melanin is superior to incomplete Freund’s adjuvant in subunit/peptide vaccines in mice

Increased IL-10+CD206+CD14+M2-like macrophages in alveolar lavage fluid of patients with small cell lung cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer