Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes

Sawada,Yu; Yoshikawa,Toshiaki; Shimomura,Manami; Iwama,Tatsuaki; Endo,Itaru; Nakatsura,Tetsuya

doi:10.3892/ijo.2014.2737

Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes

Authors:
- Yu Sawada
- Toshiaki Yoshikawa
- Manami Shimomura
- Tatsuaki Iwama
- Itaru Endo
- Tetsuya Nakatsura
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Affiliations: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan, Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan
Published online on: October 30, 2014 https://doi.org/10.3892/ijo.2014.2737
Pages: 28-36
Copyright: © Sawada et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Novel treatment modalities are required urgently in patients with hepatocellular carcinoma (HCC). A vaccine that induces cytotoxic T lymphocytes (CTLs) is an ideal strategy for cancer, and glypican-3 (GPC3) is a potential option for HCC. Blocking the programmed death-1 (PD-1)/PD-L1 pathway is a rational strategy to overcome tumor escape and tolerance toward CTLs. In the present study, we investigated whether anti-PD-1 blocking antibodies (αPD-1 Ab) enhanced the number of vaccine-induced peptide-specific CTLs in peripheral blood mononuclear cells (PBMCs) following the administration of GPC3 peptide vaccine to both patients and in a mouse model. The inhibitory receptor PD-1 was highly expressed in ex vivo GPC3-specific CTLs isolated from the PBMCs of vaccinated HCC patients. In vitro, interferon-γ induced PD-L1 expression in liver cancer cell lines. In addition, PD-1 blockade increased the number of GPC3-specific CTLs, which degranulate against liver cancer cell lines. In vivo experiments using tumor-bearing mouse models showed that the combination therapy of peptide vaccine and αPD-1 Ab suppressed tumor growth synergistically. PD-1 blockade increased the number of peptide-specific tumor-infiltrating T cells (TILs) and decreased the expression of inhibitory receptors on TILs. This study demonstrated that PD-1/PD-L1 blockade augmented the antitumor effects of a peptide vaccine by increasing the immune response of vaccine-induced CTLs, and provided a foundation for the clinical development of a combination therapy using a GPC3 peptide vaccine and αPD-1 Ab.

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1	Breous E and Thimme R: Potential of immunotherapy for hepatocellular carcinoma. J Hepatol. 54:830–834. 2011. View Article : Google Scholar
2	Greten TF, Manns MP and Korangy F: Immunotherapy of hepatocellular carcinoma. J Hepatol. 45:868–878. 2006. View Article : Google Scholar : PubMed/NCBI
3	Nakatsura T, Yoshitake Y, Senju S, et al: Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem Biophys Res Commun. 306:16–25. 2003. View Article : Google Scholar : PubMed/NCBI
4	Capurro M, Wanless IR, Sherman M, et al: Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 125:89–97. 2003. View Article : Google Scholar : PubMed/NCBI
5	Nakatsura T, Komori H, Kubo T, et al: Mouse homologue of a novel human oncofetal antigen, glypican-3, evokes T-cell-mediated tumor rejection without autoimmune reactions in mice. Clin Cancer Res. 10:8630–8640. 2004. View Article : Google Scholar
6	Komori H, Nakatsura T, Senju S, et al: Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res. 12:2689–2697. 2006. View Article : Google Scholar : PubMed/NCBI
7	Shirakawa H, Suzuki H, Shimomura M, et al: Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma. Cancer Sci. 100:1403–1407. 2009. View Article : Google Scholar : PubMed/NCBI
8	Sawada Y, Yoshikawa T, Nobuoka D, et al: Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res. 18:3686–3696. 2012. View Article : Google Scholar
9	Yoshikawa T, Nakatsugawa M, Suzuki S, et al: HLA-A2-restricted glypican-3 peptide-specific CTL clones induced by peptide vaccine show high avidity and antigen-specific killing activity against tumor cells. Cancer Sci. 102:918–925. 2011. View Article : Google Scholar
10	Agata Y, Kawasaki A, Nishimura H, et al: Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 8:765–772. 1996. View Article : Google Scholar : PubMed/NCBI
11	Freeman GJ, Long AJ, Iwai Y, et al: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 192:1027–1034. 2000. View Article : Google Scholar : PubMed/NCBI
12	Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T and Minato N: Invovement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 99:12294–12297. 2002.PubMed/NCBI
13	Iwai Y, Terawaki S and Honjo T: PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 17:133–144. 2005. View Article : Google Scholar : PubMed/NCBI
14	Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 366:2443–2454. 2012. View Article : Google Scholar : PubMed/NCBI
15	Wolchok JD, Kluger H, Callahan MK, et al: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 369:122–133. 2013. View Article : Google Scholar : PubMed/NCBI
16	Shi F, Shi M, Zeng Z, et al: PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer. 128:887–896. 2011. View Article : Google Scholar : PubMed/NCBI
17	Gao Q, Wang XY, Qiu SJ, et al: Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 15:971–979. 2009. View Article : Google Scholar : PubMed/NCBI
18	McGray AJ, Bernard D, Hallett R, et al: Combined vaccination and immunostimulatory antibodies provides durable cure of murine melanoma and induces transcriptional changes associated with positive outcome in human melanoma patients. Oncoimmunology. 1:419–431. 2012. View Article : Google Scholar
19	Mkrtichyan M, Najjar YG, Raulfs EC, et al: Anti-PD-1 synergizes with cyclophosphamide to induce potent antitumor vaccine effects through novel mechanisms. Eur J Immunol. 41:2977–2986. 2011. View Article : Google Scholar : PubMed/NCBI
20	Duraiswamy J, Kaluza KM, Freeman GJ and Coukos G: Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine efficacy restorres T cell rejection function in tumors. Cancer Res. 73:3591–3603. 2013. View Article : Google Scholar : PubMed/NCBI
21	Fourcade J, Sun Z, Pagliano O, et al: PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8⁺ T cells induced by melanoma vaccines. Cancer Res. 74:1045–1055. 2014. View Article : Google Scholar : PubMed/NCBI
22	Nobuoka D, Yoshikawa T, Takahashi M, et al: Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy. Cancer Immunol Immunother. 62:639–652. 2013. View Article : Google Scholar
23	Li B, VanRoey M, Wang C, Chen TH, Korman A and Jooss K: Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor - secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin Cancer Res. 15:1623–1634. 2009. View Article : Google Scholar
24	Iwama T, Horie K, Yoshikawa T, et al: Identification of an H2-K^b or H2-D^b restricted and glypican-3-derived cytotoxic T-lymphocyte epitope peptide. Int J Oncol. 42:831–838. 2013.
25	Peng W, Liu C, Xu C, et al: PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res. 72:5209–5218. 2012. View Article : Google Scholar : PubMed/NCBI
26	Tada Y, Yoshikawa T, Shimomura M, et al: Analysis of cytotoxic T lymphocytes from a patient with hepatocellular carcinoma who showed a clinical response to vaccination with a glypican-3-derived peptide. Int J Oncol. 43:1019–1026. 2013.
27	Wong RM, Scotland RR, Lau RL, et al: Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol. 19:1223–1234. 2007. View Article : Google Scholar : PubMed/NCBI
28	Mizukoshi E, Nakamoto Y, Arai K, et al: Comparative analysis of various tumor-associated antigen-specific T-cell responses in patients with hepatocellular carcinoma. Hepatology. 53:1206–1216. 2011. View Article : Google Scholar : PubMed/NCBI
29	Butterfield LH, Ribas A, Meng WS, et al: T-cell responses to HLA-A^*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res. 9:5902–5908. 2003.PubMed/NCBI
30	Butterfield LH, Ribas A, Dissette VB, et al: A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res. 12:2817–2825. 2006. View Article : Google Scholar
31	Greten TF, Forner A, Korangy F, et al: A phase II open trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer. 10:2092010. View Article : Google Scholar : PubMed/NCBI
32	Capurro MI, Xiang YY, Lobe C and Filmus J: Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res. 65:6245–6254. 2005. View Article : Google Scholar : PubMed/NCBI
33	Feng M, Gao W, Wang R, et al: Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci USA. 110:E1083–E1091. 2013. View Article : Google Scholar : PubMed/NCBI
34	Nagao M, Nakajima Y, Hisanaga M, et al: The alteration of Fas receptor and ligand system in hepatocellular carcinomas: how do hepatoma cells escape from the host immune surveillance in vivo? Hepatology. 30:413–421. 1999. View Article : Google Scholar : PubMed/NCBI
35	Chen C, Zhang C, Zhuang G, et al: Decoy receptor 3 overexpression and immunologic tolerance in hepatocellular carcinoma (HCC) development. Cancer Invest. 26:965–974. 2008. View Article : Google Scholar : PubMed/NCBI
36	Xu Y, Li H, Gao RL, Adeyemo O, Itkin M and Kaplan DE: Expansion of interferon-gamma-producing multifunctional CD4⁺ T-cells and dysfunctional CD8⁺ T-cells by glypican-3 peptide library in hepatocellular carcinoma patients. Clin Immunol. 139:302–313. 2011. View Article : Google Scholar : PubMed/NCBI
37	Hailemichael Y, Dai Z, Jaffarzad N, et al: Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell sequestration, dysfunction and deletion. Nat Med. 19:465–472. 2013. View Article : Google Scholar : PubMed/NCBI
38	Woo SR, Turnis ME, Goldberg MV, et al: Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72:917–927. 2012. View Article : Google Scholar : PubMed/NCBI
39	Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al: Tumor-infiltrating NY-ESO-1-specific CD8⁺ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci USA. 107:7875–7880. 2010. View Article : Google Scholar : PubMed/NCBI
40	Sierro SR, Donda A, Perret R, et al: Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces antitumor immunity. Eur J Immunol. 41:2217–2228. 2011. View Article : Google Scholar : PubMed/NCBI