Top

Published in:

Open Access 01-07-2020 | Acute Myeloid Leukemia | Original Article

Cancer testis antigen Cyclin A1 harbors several HLA-A*02:01-restricted T cell epitopes, which are presented and recognized in vivo

Authors: Anja Tatjana Teck, Sabrina Urban, Petra Quass, Annika Nelde, Heiko Schuster, Anne Letsch, Antonia Busse, Juliane Sarah Walz, Ulrich Keilholz, Sebastian Ochsenreither

Published in: Cancer Immunology, Immunotherapy | Issue 7/2020

Abstract

Cyclin A1 is a promising antigen for T cell therapy being selectively expressed in high-grade ovarian cancer (OC) and acute myeloid leukemia (AML) stem cells. For adoptive T cell therapy, a single epitope has to be selected, with high affinity to MHC class I and adequate processing and presentation by malignant cells to trigger full activation of specific T cells. In silico prediction with three algorithms indicated 13 peptides of Cyclin A1 9 to 11 amino acids of length to have high affinity to HLA-A*02:01. Ten of them proved to be affine in an HLA stabilization assay using TAP-deficient T2 cells. Their immunogenicity was assessed by repetitive stimulation of CD8⁺ T cells from two healthy donors with single-peptide-pulsed dendritic cells or monocytes. Intracellular cytokine staining quantified the enrichment of peptide-specific functional T cells. Seven peptides were immunogenic, three of them against both donors. Specific cell lines were cloned and used in killing assays to demonstrate recognition of endogenous Cyclin A1 in the HLA-A*02:01-positive AML cell line THP-1. Immunopeptidome analysis based on direct isolation of HLA-presented peptides by mass spectrometry of primary AML and OC samples identified four naturally presented epitopes of Cyclin A1. The immunopeptidome of HeLa cells transfected with Cyclin A1 and HLA-A*02:01 revealed six Cyclin A1-derived HLA ligands. Epitope p410–420 showed high affinity to HLA-A*02:01 and immunogenicity in both donors. It proved to be naturally presented on primary AML blast and provoked spontaneous functional response of T cells from treatment naïve OC and, therefore, warrants further development for clinical application.

Chae YK, Arya A, Iams W, Cruz MR, Chandra S, Choi J, Giles F (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer. https://doi.org/10.1186/s40425-018-0349-3CrossRefPubMedPubMedCentral

Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359(6382):1350–1355. https://doi.org/10.1126/science.aar4060CrossRefPubMedPubMedCentral

Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, Roshal M, Maslak P, Davila M, Brentjens RJ, Sadelain M (2018) Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 378(5):449–459. https://doi.org/10.1056/NEJMoa1709919CrossRefPubMedPubMedCentral

Robbins PF, Kassim SH, Tran TL, Crystal JS, Morgan RA, Feldman SA, Yang JC, Dudley ME, Wunderlich JR, Sherry RM, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Li YF, El-Gamil M, Rosenberg SA (2015) A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res: Off J Am Assoc Cancer Res 21(5):1019–1027. https://doi.org/10.1158/1078-0432.CCR-14-2708CrossRef

Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol: Off J Am Soc Clin Oncol 29(7):917–924. https://doi.org/10.1200/JCO.2010.32.2537CrossRef

Schmitt TM, Stromnes IM, Chapuis AG, Greenberg PD (2015) New strategies in engineering t-cell receptor gene-modified t cells to more effectively target malignancies. Clin Cancer Res: Off J Am Assoc Cancer Res 21(23):5191–5197. https://doi.org/10.1158/1078-0432.CCR-15-0860CrossRef

Schmitt TM, Aggen DH, Ishida-Tsubota K, Ochsenreither S, Kranz DM, Greenberg PD (2017) Generation of higher affinity T cell receptors by antigen-driven differentiation of progenitor T cells in vitro. Nat Biotechnol 35(12):1188–1195. https://doi.org/10.1038/nbt.4004CrossRefPubMedPubMedCentral

Gomez-Eerland R, Nuijen B, Heemskerk B, van Rooij N, van den Berg JH, Beijnen JH, Uckert W, Kvistborg P, Schumacher TN, Haanen JB, Jorritsma A (2014) Manufacture of gene-modified human T-cells with a memory stem/central memory phenotype. Hum Gene Ther Methods 25(5):277–287. https://doi.org/10.1089/hgtb.2014.004CrossRefPubMedPubMedCentral

Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR (2008) Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Investig 118(1):294–305. https://doi.org/10.1172/JCI32103CrossRefPubMed

10.

Kunert A, Obenaus M, Lamers CHJ, Blankenstein T, Debets R (2017) T-cell receptors for clinical therapy: in vitro assessment of toxicity risk. Clin Cancer Res: Off J Am Assoc Cancer Res 23(20):6012–6020. https://doi.org/10.1158/1078-0432.CCR-17-1012CrossRef

11.

Ochsenreither S, Majeti R, Schmitt T, Stirewalt D, Keilholz U, Loeb KR, Wood B, Choi YE, Bleakley M, Warren EH, Hudecek M, Akatsuka Y, Weissman IL, Greenberg PD (2012) Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen. Blood 119(23):5492–5501. https://doi.org/10.1182/blood-2011-07-365890CrossRefPubMedPubMedCentral

12.

Snauwaert S, Vanhee S, Goetgeluk G, Verstichel G, Van Caeneghem Y, Velghe I, Philippe J, Berneman ZN, Plum J, Taghon T, Leclercq G, Thielemans K, Kerre T, Vandekerckhove B (2012) RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. Haematologica 97(10):1539–1547. https://doi.org/10.3324/haematol.2012.065581CrossRefPubMedPubMedCentral

13.

Neidert MC, Kowalewski DJ, Silginer M, Kapolou K, Backert L, Freudenmann LK, Peper JK, Marcu A, Wang SS, Walz JS, Wolpert F, Rammensee HG, Henschler R, Lamszus K, Westphal M, Roth P, Regli L, Stevanovic S, Weller M, Eisele G (2018) The natural HLA ligandome of glioblastoma stem-like cells: antigen discovery for T cell-based immunotherapy. Acta Neuropathol 135(6):923–938. https://doi.org/10.1007/s00401-018-1836-9CrossRefPubMed

14.

Vigneron N, Van den Eynde BJ (2011) Insights into the processing of MHC class I ligands gained from the study of human tumor epitopes. Cell Mol Life Sci:CMLS 68(9):1503–1520. https://doi.org/10.1007/s00018-011-0658-xCrossRefPubMed

15.

Arsenic R, Braicu EI, Letsch A, Dietel M, Sehouli J, Keilholz U, Ochsenreither S (2015) Cancer-testis antigen cyclin A1 is broadly expressed in ovarian cancer and is associated with prolonged time to tumor progression after platinum-based therapy. BMC Cancer 15:784. https://doi.org/10.1186/s12885-015-1824-6CrossRefPubMedPubMedCentral

16.

Wolgemuth DJ (2011) Function of the A-type cyclins during gametogenesis and early embryogenesis. Results Probl Cell Differ 53:391–413. https://doi.org/10.1007/978-3-642-19065-0_17CrossRefPubMedPubMedCentral

17.

Yang R, Morosetti R, Koeffler HP (1997) Characterization of a second human Cyclin A that is highly expressed in testis and in several leukemic cell lines. Can Res 57(5):913–920

18.

Liao C, Wang XY, Wei HQ, Li SQ, Merghoub T, Pandolfi PP, Wolgemuth DJ (2001) Altered myelopoiesis and the development of acute myeloid leukemia in transgenic mice overexpressing Cyclin A1. Proc Natl Acad Sci USA 98(12):6853–6858. https://doi.org/10.1073/pnas.121540098CrossRefPubMedPubMedCentral

19.

Parker KC, Bednarek MA, Coligan JE (1994) Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol 152(1):163–175PubMed

20.

Kim Y, Ponomarenko J, Zhu Z, Tamang D, Wang P, Greenbaum J, Lundegaard C, Sette A, Lund O, Bourne PE, Nielsen M, Peters B (2012) Immune epitope database analysis resource. Nucl Acids Res 40(Web Server issue):W525–W530. https://doi.org/10.1093/nar/gks438CrossRefPubMedPubMedCentral

21.

Rammensee HG, Bachmann J, Emmerich NPN, Bachor OA, Stevanovic S (1999) SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50(3–4):213–219. https://doi.org/10.1007/s002510050595CrossRefPubMed

22.

Berlin C, Kowalewski DJ, Schuster H, Mirza N, Walz S, Handel M, Schmid-Horch B, Salih HR, Kanz L, Rammensee HG, Stevanovic S, Stickel JS (2015) Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy. Leukemia 29(3):647–659. https://doi.org/10.1038/leu.2014.233CrossRefPubMed

23.

Kowalewski DJ, Stevanovic S (2013) Biochemical large-scale identification of MHC class I ligands. Methods Mol Biol 960:145–157. https://doi.org/10.1007/978-1-62703-218-6_12CrossRefPubMed

24.

Kowalewski DJ, Schuster H, Backert L, Berlin C, Kahn S, Kanz L, Salih HR, Rammensee HG, Stevanovic S, Stickel JS (2015) HLA ligandome analysis identifies the underlying specificities of spontaneous antileukemia immune responses in chronic lymphocytic leukemia (CLL). Proc Natl Acad Sci USA 112(2):E166–175. https://doi.org/10.1073/pnas.1416389112CrossRefPubMed

25.

Nelde A, Kowalewski DJ, Backert L, Schuster H, Werner JO, Klein R, Kohlbacher O, Kanz L, Salih HR, Rammensee HG, Stevanovic S, Walz JS (2018) HLA ligandome analysis of primary chronic lymphocytic leukemia (CLL) cells under lenalidomide treatment confirms the suitability of lenalidomide for combination with T-cell-based immunotherapy. Oncoimmunology 7(4):e1316438. https://doi.org/10.1080/2162402X.2017.1316438CrossRefPubMedPubMedCentral

26.

Eng JK, McCormack AL, Yates JR (1994) An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database. J Am Soc Mass Spectrom 5(11):976–989. https://doi.org/10.1016/1044-0305(94)80016-2CrossRefPubMed

27.

Kall L, Canterbury JD, Weston J, Noble WS, MacCoss MJ (2007) Semi-supervised learning for peptide identification from shotgun proteomics datasets. Nat Methods 4(11):923–925. https://doi.org/10.1038/nmeth1113CrossRefPubMed

28.

Nielsen M, Andreatta M (2016) NetMHCpan-3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets. Genome Med 8(1):33. https://doi.org/10.1186/s13073-016-0288-xCrossRefPubMedPubMedCentral

29.

Ho WY, Nguyen HN, Wolfl M, Kuball J, Greenberg PD (2006) In vitro methods for generating CD⁸⁺ T-cell clones for immunotherapy from the naive repertoire. J Immunol Methods 310(1–2):40–52. https://doi.org/10.1016/j.jim.2005.11.023CrossRefPubMed

30.

Stanke J, Hoffmann C, Erben U, von Keyserling H, Stevanovic S, Cichon G, Schneider A, Kaufmann AM (2010) A flow cytometry-based assay to assess minute frequencies of CD⁸⁺ T cells by their cytolytic function. J Immunol Methods 360(1–2):56–65. https://doi.org/10.1016/j.jim.2010.06.005CrossRefPubMed

31.

Reinherz EL (2015) alphabeta TCR-mediated recognition: relevance to tumor-antigen discovery and cancer immunotherapy. Cancer Immunol Res 3(4):305–312. https://doi.org/10.1158/2326-6066.CIR-15-0042CrossRefPubMedPubMedCentral

32.

Hu Z, Wang J, Wan Y, Zhu L, Ren X, Qiu S, Ren Y, Yuan S, Ding X, Chen J, Qiu C, Sun J, Zhang X, Xiang J, Qiu C, Xu J (2014) Boosting functional avidity of CD8+ T cells by vaccinia virus vaccination depends on intrinsic T-cell MyD88 expression but not the inflammatory milieu. J Virol 88(10):5356–5368. https://doi.org/10.1128/JVI.03664-13CrossRefPubMedPubMedCentral

33.

Engels B, Engelhard VH, Sidney J, Sette A, Binder DC, Liu RB, Kranz DM, Meredith SC, Rowley DA, Schreiber H (2013) Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell 23(4):516–526. https://doi.org/10.1016/j.ccr.2013.03.018CrossRefPubMedPubMedCentral

34.

Schmidt J, Neumann-Haefelin C, Altay T, Gostick E, Price DA, Lohmann V, Blum HE, Thimme R (2011) Immunodominance of HLA-A2-restricted hepatitis C virus-specific CD⁸⁺ T cell responses is linked to naive-precursor frequency. J Virol 85(10):5232–5236. https://doi.org/10.1128/JVI.00093-11CrossRefPubMedPubMedCentral

35.

Ochsenreither S, Fusi A, Geikowski A, Stather D, Busse A, Stroux A, Letsch A, Keilholz U (2012) Wilms' tumor protein 1 (WT1) peptide vaccination in AML patients: predominant TCR CDR3beta sequence associated with remission in one patient is detectable in other vaccinated patients. Cancer Immunol Immunother: CII 61(3):313–322. https://doi.org/10.1007/s00262-011-1099-yCrossRefPubMed

36.

van Bergen CAM, van der Steen DM, Kester MGD, Koning MT, van Veelen PA, Griffioen M, Falkenburg JHF, Heemskerk MHM, Veelken H, Navarrete MA (2016) Endogenous immunoglobulin-derived neoepitopes are processed and form a sizeable fraction of the HLA class I ligandome of human lymphoma cells. Blood 128(22):914CrossRef

37.

Walz S, Stickel JS, Kowalewski DJ, Schuster H, Weisel K, Backert L, Kahn S, Nelde A, Stroh T, Handel M, Kohlbacher O, Kanz L, Salih HR, Rammensee HG, Stevanovic S (2015) The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy. Blood 126(10):1203–1213. https://doi.org/10.1182/blood-2015-04-640532CrossRefPubMedPubMedCentral

Title: Cancer testis antigen Cyclin A1 harbors several HLA-A*02:01-restricted T cell epitopes, which are presented and recognized in vivo
Authors: Anja Tatjana Teck
Sabrina Urban
Petra Quass
Annika Nelde
Heiko Schuster
Anne Letsch
Antonia Busse
Juliane Sarah Walz
Ulrich Keilholz
Sebastian Ochsenreither
Publication date: 01-07-2020
Publisher: Springer Berlin Heidelberg
Keywords: Acute Myeloid Leukemia
Ovarian Cancer
Ovarian Cancer
Published in: Cancer Immunology, Immunotherapy / Issue 7/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02519-6

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 7/2020

Differential expression of Tim-3, PD-1, and CCR5 on peripheral T and B lymphocytes in hepatitis C virus-related hepatocellular carcinoma and their impact on treatment outcomes

Adenosine-producing regulatory B cells in head and neck cancer

Tumor-associated antigen-based personalized dendritic cell vaccine in solid tumor patients

Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort

Genome-wide association study of genetic variations associated with treatment failure after intravesical bacillus Calmette–Guérin therapy for non-muscle invasive bladder cancer

Comprehensive landscape of immune-checkpoints uncovered in clear cell renal cell carcinoma reveals new and emerging therapeutic targets

Keynote webinar | Spotlight on antibody–drug conjugates in cancer