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Open Access 01-07-2017 | Original Article

IDO and galectin-3 hamper the ex vivo generation of clinical grade tumor-specific T cells for adoptive cell therapy in metastatic melanoma

Authors: Sara M. Melief, Marten Visser, Sjoerd H. van der Burg, Els M. E. Verdegaal

Published in: Cancer Immunology, Immunotherapy | Issue 7/2017

Abstract

Adoptive T cell transfer (ACT) with ex vivo-expanded tumor-reactive T cells proved to be successful for the treatment of metastatic melanoma patients. Mixed lymphocyte tumor cell cultures (MLTC) can be used to generate tumor-specific T cells for ACT; however, in a number of cases tumor-reactive T cell, expansion is far from optimal. We hypothesized that this is due to tumor intrinsic and extrinsic factors and aimed to identify and manipulate these factors so to optimize our clinical, GMP-compliant MLTC protocol. We found that the tumor cell produced IDO and/or galectin-3, and the accumulation of CD4⁺CD25^hiFoxP3⁺ T cells suppressed the expansion of tumor-specific T cells in the MLTC. Strategies to eliminate CD4⁺CD25^hiFoxP3⁺ T cells during culture required the depletion of the whole CD4⁺ T cell population and were found to be undesirable. Blocking of IDO and galectin-3 was feasible and resulted in improved efficiency of the MLTC. Implementation of these findings in clinical protocols for ex vivo expansion of tumor-reactive T cells holds promise for an increased therapeutic potential of adoptive cell transfer treatments with tumor-specific T cells.

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Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE (1994) Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst 86(15):1159–1166CrossRefPubMed

Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM, Dengel LT, Patterson JW, Slingluff CL Jr (2012) Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res 72(5):1070–1080. doi:10.1158/0008-5472.can-11-3218 CrossRefPubMedPubMedCentral

Kluger HM, Zito CR, Barr ML, Baine MK, Chiang VLS, Sznol M, Rimm DL, Chen L, Jilaveanu LB (2015) Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin Cancer Res 21(13):3052–3060. doi:10.1158/1078-0432.ccr-14-3073 CrossRefPubMedPubMedCentral

Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26(32):5233–5239. doi:10.1200/JCO.2008.16.5449 CrossRefPubMedPubMedCentral

Verdegaal EM, Visser M, Ramwadhdoebe TH, van der Minne CE, van Steijn JA, Kapiteijn E, Haanen JB, van der Burg SH, Nortier JW, Osanto S (2011) Successful treatment of metastatic melanoma by adoptive transfer of blood-derived polyclonal tumor-specific CD4+ and CD8+ T cells in combination with low-dose interferon-alpha. Cancer Immunol Immunother 60(7):953–963. doi:10.1007/s00262-011-1004-8 CrossRefPubMedPubMedCentral

Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R, Calis JJ, Behjati S, Velds A, Hilkmann H, Atmioui DE, Visser M, Stratton MR, Haanen JB, Spits H, van der Burg SH, Schumacher TN (2015) High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat Med 21(1):81–85. doi:10.1038/nm.3773 CrossRefPubMed

Verdegaal EM, de Miranda NF, Visser M, Harryvan T, van Buuren MM, Andersen RS, Hadrup SR, van der Minne CE, Schotte R, Spits H, Haanen JB, Kapiteijn EH, Schumacher TN, van der Burg SH (2016) Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature 536(7614):91–95. doi:10.1038/nature18945 CrossRefPubMed

Vereecken P, Debray C, Petein M, Awada A, Lalmand MC, Laporte M, Van Den Heule B, Verhest A, Pochet R, Heenen M (2005) Expression of galectin-3 in primary and metastatic melanoma: immunohistochemical studies on human lesions and nude mice xenograft tumors. Arch Dermatol Res 296(8):353–358. doi:10.1007/s00403-004-0536-6 CrossRefPubMed

Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117(5):1147–1154. doi:10.1172/jci31178 CrossRefPubMedPubMedCentral

10.

Brody JR, Costantino CL, Berger AC, Sato T, Lisanti MP, Yeo CJ, Emmons RV, Witkiewicz AK (2009) Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle 8(12):1930–1934CrossRefPubMed

11.

Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114(8):1537–1544. doi:10.1182/blood-2008-12-195792 CrossRefPubMedPubMedCentral

12.

Braeuer RR, Shoshan E, Kamiya T, Bar-Eli M (2012) The sweet and bitter sides of galectins in melanoma progression. Pigment Cell Melanoma Res 25(5):592–601. doi:10.1111/j.1755-148X.2012.01026.x CrossRefPubMed

13.

Liu FT (2005) Regulatory roles of galectins in the immune response. Int Arch Allergy Immunol 136(4):385–400. doi:10.1159/000084545 CrossRefPubMed

14.

Liu FT, Rabinovich GA (2005) Galectins as modulators of tumour progression. Nat Rev Cancer 5(1):29–41. doi:10.1038/nrc1527 CrossRefPubMed

15.

Cedeno-Laurent F, Opperman M, Barthel SR, Kuchroo VK, Dimitroff CJ (2012) Galectin-1 triggers an immunoregulatory signature in Th cells functionally defined by IL-10 expression. J Immunol 188(7):3127–3137. doi:10.4049/jimmunol.1103433 CrossRefPubMedPubMedCentral

16.

Demotte N, Wieers G, Van Der Smissen P, Moser M, Schmidt C, Thielemans K, Squifflet JL, Weynand B, Carrasco J, Lurquin C, Courtoy PJ, van der Bruggen P (2010) A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Res 70(19):7476–7488. doi:10.1158/0008-5472.can-10-0761 CrossRefPubMed

17.

Kouo T, Huang L, Pucsek AB, 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 Immunol Res 3(4):412–423. doi:10.1158/2326-6066.cir-14-0150 CrossRefPubMedPubMedCentral

18.

Zubieta MR, Furman D, Barrio M, Bravo AI, Domenichini E, Mordoh J (2006) Galectin-3 expression correlates with apoptosis of tumor-associated lymphocytes in human melanoma biopsies. Am J Pathol 168(5):1666–1675. doi:10.2353/ajpath.2006.050971 CrossRefPubMedPubMedCentral

19.

Chen HY, Fermin A, Vardhana S, Weng IC, Lo KF, Chang EY, Maverakis E, Yang RY, Hsu DK, Dustin ML, Liu FT (2009) Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse. Proc Natl Acad Sci USA 106(34):14496–14501. doi:10.1073/pnas.0903497106 CrossRefPubMedPubMedCentral

20.

Hsu DK, Chen HY, Liu FT (2009) Galectin-3 regulates T-cell functions. Immunol Rev 230(1):114–127. doi:10.1111/j.1600-065X.2009.00798.x CrossRefPubMed

21.

Perillo NL, Pace KE, Seilhamer JJ, Baum LG (1995) Apoptosis of T cells mediated by galectin-1. Nature 378(6558):736–739. doi:10.1038/378736a0 CrossRefPubMed

22.

Taylor MW, Feng GS (1991) Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 5(11):2516–2522PubMed

23.

Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281(5380):1191–1193CrossRefPubMed

24.

Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176(11):6752–6761CrossRefPubMed

25.

Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183(4):2475–2483. doi:10.4049/jimmunol.0900986 CrossRefPubMedPubMedCentral

26.

Xu L, Xu W, Jiang Z, Zhang F, Chu Y, Xiong S (2009) Depletion of CD4(+)CD25(high) regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy. Cancer Biol Ther 8(1):66–72CrossRefPubMed

27.

Li Y, Yee C (2008) IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes. Blood 111(1):229–235. doi:10.1182/blood-2007-05-089375 CrossRefPubMedPubMedCentral

28.

Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW (2004) Autoreactive T cells in healthy individuals. J Immunol 172(10):5967–5972CrossRefPubMed

29.

Wang HY, Peng G, Guo Z, Shevach EM, Wang RF (2005) Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4+ regulatory T cells. J Immunol 174(5):2661–2670CrossRefPubMed

30.

Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, Shevach EM, Wang RF (2004) Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20(1):107–118CrossRefPubMed

31.

Herin M, Lemoine C, Weynants P, Vessiere F, Van Pel A, Knuth A, Devos R, Boon T (1987) Production of stable cytolytic T-cell clones directed against autologous human melanoma. Int J Cancer 39(3):390–396CrossRefPubMed

32.

Braun D, Longman RS, Albert ML (2005) A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood 106(7):2375–2381. doi:10.1182/blood-2005-03-0979 CrossRefPubMedPubMedCentral

33.

Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, Marshall B, Chandler P, Antonia SJ, Burgess R, Slingluff CL Jr, Mellor AL (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297(5588):1867–1870. doi:10.1126/science.1073514 CrossRefPubMed

34.

Wong SB, Bos R, Sherman LA (2008) Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J Immunol 180(5):3122–3131CrossRefPubMed

35.

Bos R, Sherman LA (2010) CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res 70(21):8368–8377. doi:10.1158/0008-5472.CAN-10-1322 CrossRefPubMedPubMedCentral

36.

Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, Blasberg R, Yagita H, Muranski P, Antony PA, Restifo NP, Allison JP (2010) Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 207(3):637–650. doi:10.1084/jem.20091918 CrossRefPubMedPubMedCentral

37.

Friedman KM, Prieto PA, Devillier LE, Gross CA, Yang JC, Wunderlich JR, Rosenberg SA, Dudley ME (2012) Tumor-specific CD4+ melanoma tumor-infiltrating lymphocytes. J Immunother 35(5):400–408. doi:10.1097/CJI.0b013e31825898c5 CrossRefPubMed

38.

Kitano S, Tsuji T, Liu C, Hirschhorn-Cymerman D, Kyi C, Mu Z, Allison JP, Gnjatic S, Yuan JD, Wolchok JD (2013) Enhancement of tumor-reactive cytotoxic CD4+ T cell responses after ipilimumab treatment in four advanced melanoma patients. Cancer Immunol Res 1(4):235–244. doi:10.1158/2326-6066.CIR-13-0068 CrossRefPubMed

39.

Wang RF, Wang X, Rosenberg SA (1999) Identification of a novel major histocompatibility complex class II-restricted tumor antigen resulting from a chromosomal rearrangement recognized by CD4(+) T cells. J Exp Med 189(10):1659–1668CrossRefPubMedPubMedCentral

40.

Chevolet I, Speeckaert R, Schreuer M, Neyns B, Krysko O, Bachert C, Hennart B, Allorge D, van Geel N, Van Gele M, Brochez L (2015) Characterization of the immune network of IDO, tryptophan metabolism, PD-L1, and in circulating immune cells in melanoma. Oncoimmunology 4 (3):e982382. doi:10.4161/2162402x.2014.982382 CrossRefPubMedPubMedCentral

41.

Moon YW, Hajjar J, Hwu P, Naing A (2015) Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer 3:51. doi:10.1186/s40425-015-0094-9. (eCollection 2015) CrossRefPubMedPubMedCentral

42.

Lob S, Konigsrainer A, Schafer R, Rammensee HG, Opelz G, Terness P (2008) Levo- but not dextro-1-methyl tryptophan abrogates the IDO activity of human dendritic cells. Blood 111(4):2152–2154. doi:10.1182/blood-2007-10-116111 CrossRefPubMed

43.

Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH (2007) Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67(2):792–801. doi:10.1158/0008-5472.can-06-2925 CrossRefPubMed

44.

Cheever MA (2008) Twelve immunotherapy drugs that could cure cancers. Immunol Rev 222:357–368. doi:10.1111/j.1600-065X.2008.00604.x CrossRefPubMed

45.

http://www.galectintherapeutics.com. Accessed 20 Dec 2016

46.

Harrison SA, Marri SR, Chalasani N, Kohli R, Aronstein W, Thompson GA, Irish W, Miles MV, Xanthakos SA, Lawitz E, Noureddin M, Schiano TD, Siddiqui M, Sanyal A, Neuschwander-Tetri BA, Traber PG (2016) Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther 44(11–12):1183–1198. doi:10.1111/apt.13816 CrossRefPubMed

47.

Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA (2004) Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; a potential mechanism of tumor-immune privilege. Cancer Cell 5(3):241–251CrossRefPubMed

Title: IDO and galectin-3 hamper the ex vivo generation of clinical grade tumor-specific T cells for adoptive cell therapy in metastatic melanoma
Authors: Sara M. Melief
Marten Visser
Sjoerd H. van der Burg
Els M. E. Verdegaal
Publication date: 01-07-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 7/2017
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-1995-x

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