We herein report the identification of an HLA-A2 supertype-restricted epitope peptide derived from hypoxia-inducible protein 2 (HIG2), which is known to be a diagnostic marker and a potential therapeutic target for renal cell carcinoma. Among several candidate peptides predicted by the HLA-binding prediction algorithm, HIG2-9-4 peptide (VLNLYLLGV) was able to effectively induce peptide-specific cytotoxic T lymphocytes (CTLs). The established HIG2-9-4 peptide-specific CTL clone produced interferon-γ (IFN-γ) in response to HIG2-9-4 peptide-pulsed HLA-A*02:01-positive cells, as well as to cells in which HLA-A*02:01 and HIG2 were exogenously introduced. Moreover, the HIG2-9-4 peptide-specific CTL clone exerted cytotoxic activity against HIG2-expressing HLA-A*02:01-positive renal cancer cells, thus suggesting that the HIG2-9-4 peptide is naturally presented on HLA-A*02:01 of HIG-2-expressing cancer cells and is recognized by CTLs. Furthermore, we found that the HIG2-9-4 peptide could also induce CTLs under HLA-A*02:06 restriction. Taken together, these findings indicate that the HIG2-9-4 peptide is a novel HLA-A2 supertype-restricted epitope peptide that could be useful for peptide-based immunotherapy against cancer cells with HIG2 expression.
References
[1]
Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60: 277–300.
[2]
Cohen HT, McGovern FJ (2005) Renal-cell carcinoma. N Engl J Med 353: 2477–2490.
[3]
National Comprehensive Cancer Network (2012) NCCN Clinical Practice Guidelines in Oncology. Kidney Cancer. Version2.2012. Available: http://www.tri-kobe.org/nccn/guideline/u？rological/english/kidney.pdf
[4]
Patil S, Ishill N, Deluca J, Motzer RJ (2010) Stage migration and increasing proportion of favorable-prognosis metastatic renal cell carcinoma patients: implications for clinical trial design and interpretation. Cancer 116: 347–354.
[5]
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, et al. (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378: 1931–1939.
[6]
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356: 115–124.
[7]
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, et al. (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27: 3584–3590.
[8]
Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, et al. (2009) Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 27: 1280–1289.
[9]
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, et al. (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356: 2271–2281.
[10]
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, et al. (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370: 2103–2111.
[11]
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, et al. (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372: 449–456.
[12]
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, et al. (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116: 4256–4265.
[13]
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, et al. (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28: 1061–1068.
[14]
McDermott DF (2009) Immunotherapy of metastatic renal cell carcinoma. Cancer 115: 2298–2305.
[15]
Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, et al. (1993) Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11: 1969–1977.
[16]
Atzpodien J, Kirchner H, Jonas U, Bergmann L, Schott H, et al. (2004) Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J Clin Oncol 22: 1188–1194.
[17]
Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, et al. (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13: 688–696.
[18]
Bleumer I, Tiemessen DM, Oosterwijk-Wakka JC, V？ller MC, De Weijer K, et al. (2007) Preliminary analysis of patients with progressive renal cell carcinoma vaccinated with CA9-peptide-pulsed mature dendritic cells. J Immunother 30: 116–122.
[19]
Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT (2002) Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 188: 22–32.
[20]
Tsuji T, Matsuzaki J, Kelly MP, Ramakrishna V, Vitale L, et al. (2011) Antibody-targeted NY-ESO-1 to mannose receptor or DEC-205 in vitro elicits dual human CD8+ and CD4+ T cell responses with broad antigen specificity. J Immunol 186: 1218–1227.
[21]
Amato RJ, Shingler W, Goonewardena M, de Belin J, Naylor S, et al. (2009) Vaccination of renal cell cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) alone or administered in combination with interferon-α (IFN-α): a Phase 2 trial. J Immunother 32: 765–772.
[22]
Denko N, Schindler C, Koong A, Laderoute K, Green C, et al. (2000) Epigenetic regulation of gene expression in cervical cancer cells by the tumor microenvironment. Clin Cancer Res 6: 480–487.
[23]
Gimm T, Wiese M, Teschemacher B, Deggerich A, Sch？del J, et al. (2010) Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J 24: 4443–4458.
[24]
Togashi A, Katagiri T, Ashida S, Fujioka T, Maruyama O, et al. (2005) Hypoxia-inducible protein 2 (HIG2), a novel diagnostic marker for renal cell carcinoma and potential target for molecular therapy. Cancer Res 65: 4817–4826.
[25]
Seo T, Konda R, Sugimura J, Iwasaki K, Nakamura Y, et al. (2010) Expression of hypoxia-inducible protein 2 in renal cell carcinoma: A promising candidate for molecular targeting therapy. Oncol Lett 1: 697–701.
[26]
Cao K, Hollenbach J, Shi X, Shi W, Chopek M, et al. (2001) Analysis of the frequency of HLA-A, B and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. Hum Immunol 62: 1009–1030.
[27]
Itoh Y, Mizuki N, Shimada T, Azuma F, Itakura M, et al. (2005) High-throughput DNA typing of HLA-A, -B, -C, and -DRB1 loci by a PCR-SSOP-Luminex method in the Japanese population. Immunogenetics 57: 717–729.
[28]
Tsomides TJ, Aldovini A, Johnson RP, Walker BD, Young RA, et al. (1994) Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1. J Exp Med 180: 1283–1293.
[29]
Celis E, Tsai V, Crimi C, DeMars R, Wentworth PA, et al. (1994) Induction of anti-tumor cytotoxic T lymphocytes in normal humans using primary cultures and synthetic peptide epitopes. Proc Natl Acad Sci U S A 91: 2105–2109.
[30]
Uchida N, Tsunoda T, Wada S, Furukawa Y, Nakamura Y, et al. (2004) Ring finger protein (RNF) 43 as a New Target for Cancer Immunotherapy. Clin Can Res 10: 8577–8586.
[31]
Suda T, Tsunoda T, Daigo Y, Nakamura Y, Tahara H (2007) Identification of human leukocyte antigen-A24-restricted epitope peptides derived from gene products upregulated in lung and esophageal cancers as novel targets for immunotherapy. Cancer Sci 98: 1803–1808.
[32]
Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, et al. (2004) Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J Exp Med 199: 437–448.
[33]
Sidney J, Southwood S, Mann DL, Fernandez-Vina MA, Newman MJ, et al. (2001) Majority of peptides binding HLA-A*0201 with high affinity crossreact with other A2-supertype molecules. Hum Immunol 62: 1200–1216.
[34]
Fleischhauer K, Tanzarella S, Russo V, Sensi ML, van der Bruggen P, et al. (1997) Functional heterogeneity of HLA-A*02 subtypes revealed by presentation of a MAGE-3-encoded peptide to cytotoxic T cell clones. J Immunol 159: 2513–2521.
[35]
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, et al. (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363: 411–422.
[36]
Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, et al. (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364: 2517–2526.
[37]
Boon T (1993) Tumor antigens recognized by cytolytic T lymphocytes: present perspectives for specific immunotherapy. Int J Cancer 54: 177–180.
[38]
Rimoldi D, Rubio-Godoy V, Dutoit V, Lienard D, Salvi S, et al. (2000) Efficient simultaneous presentation of NY-ESO-1/LAGE-1 primary and nonprimary open reading frame-derived CTL epitopes in melanoma. J Immunol 165: 7253–7261.
[39]
Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Topalian SL, et al. (2003) Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma. Clin Cancer Res 9: 2973–2980.
[40]
Pecher G, H？ring A, Kaiser L, Thiel E (2002) Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial. Cancer Immunol Immunother 51: 669–673.
[41]
Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10: 909–915.
[42]
Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, et al. (2010) Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 28: 4722–4729.
[43]
DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T (2012) Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482: 405–409.
[44]
Okuno K, Sugiura F, Hida JI, Tokoro T, Ishimaru E, et al. (2011) Phase I clinical trial of a novel peptide vaccine in combination with UFT/LV for metastatic colorectal cancer. Exp Ther Med 2: 73–79.
[45]
Kono K, Iinuma H, Akutsu Y, Tanaka H, Hayashi N, et al. (2012) Multicenter, phase II clinical trial of cancer vaccination for advanced esophageal cancer with three peptides derived from novel cancer-testis antigens. J Transl Med 10: 141.
[46]
Obara W, Ohsawa R, Kanehira M, Takata R, Tsunoda T, et al. (2012) Cancer peptide vaccine therapy developed from oncoantigens identified through genome-wide expression profile analysis for bladder cancer. Jpn J Clin Oncol 42: 591–600.
