Immunotherapy of hepatocellular carcinoma: is there a place for regulatory T-lymphocyte depletion?
Abstract
Immunotherapy represents a potential therapeutic option for patients with hepatocellular carcinoma (HCC), especially as secondary treatment to prevent recurrence. It has been shown that a patient’s survival is directly correlated to the type and number of tumor-infiltrating immune cells, indicating that immune responses have a direct effect on the clinical course of the disease. We have assessed the potential of immunotherapy against HCC in preclinical models of low tumor burden. An antigen-specific strategy targeting α-fetoprotein, and consisting of immunization with a DNA-based synthetic vector (DNAmAFP/704), was tested on an autochthonous model of chemical hepatocarcinogenesis and led to an important (65%) reduction of the tumor burden. A nonspecific approach of CD25+ T-cell depletion by injection of PC61 antibody was also tested on an orthotopic HCC model and led to a significant protection against tumor development. Antigen-specific immunotherapy and Treg depletion are promising strategies in physiologically relevant HCC preclinical models. Future clinical trials will demonstrate if a combination of Treg depletion with an antigen-specific immunotherapy will also translate into clinical responses in HCC patients.
Bibliography
- 1 El-Serag HB, Marrero JA, Rudolph L, Reddy KR: Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology134(6),1752–1763 (2008).
- 2 Llovet JM, Bruix J: Novel advancements in the management of hepatocellular carcinoma in 2008. J. Hepatol.48(Suppl. 1),S20–S37 (2008).
- 3 Zerbini A, Pilli M, Ferrari C, Missale G: Is there a role for immunotherapy in hepatocellular carcinoma? Dig. Liver Dis.38(4),221–225 (2006).
- 4 Sung CH, Hu CP, Hsu HC et al.: Expression of class I and class II major histocompatibility antigens on human hepatocellular carcinoma. J. Clin. Invest.83(2),421–429 (1989).
- 5 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 α-fetoprotein peptides. Clin. Cancer Res.12(9),2817–2825 (2006).
- 6 Pichard V, Royer PJ, Richou C et al.: Detection, isolation, and characterization of α-fetoprotein-specific T cell populations and clones using MHC class I multimer magnetic sorting. J. Immunother.31(3),246–253 (2008).
- 7 Zerbini A, Pilli M, Penna A et al.: Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res.66(2),1139–1146 (2006).
- 8 Gao Q, Qiu SJ, Fan J et al.: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J. Clin. Oncol.25(18),2586–2593 (2007).
- 9 Fu J, Xu D, Liu Z et al.: Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology132(7),2328–2339 (2007).
- 10 Greten TF, Manns MP, Korangy F: Immunotherapy of hepatocellular carcinoma. J. Hepatol.45(6),868–878 (2006).
- 11 Takayama T, Sekine T, Makuuchi M et al.: Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet356(9232),802–807 (2000).
- 12 Kuang M, Peng BG, Lu MD et al.: Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin. Cancer Res.10(5),1574–1579 (2004).
- 13 Cany J, Avril A, Pichard V, Aubert D, Ferry N, Conchon S: A transgenic mouse with β-galactosidase as a fetal liver self-antigen for immunotherapy studies. J. Hepatol.47(3),396–403 (2007).
- 14 McIlroy D, Barteau B, Cany J et al.: DNA/amphiphilic block copolymer nanospheres promote low-dose DNA vaccination. Mol. Ther.17(8),1473–1481 (2009).
- 15 Cany J, Barteau B, Tran L et al.: AFP-specific immunotherapy impairs growth of autochthonous hepatocellular carcinoma in mice. J. Hepatol.54(1),115–121 (2011).
- 16 Shimizu J, Yamazaki S, Sakaguchi S: Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol.163(10),5211–5218 (1999).
- 17 Greten TF, Ormandy LA, Fikuart A et al.: Low-dose cyclophosphamide treatment impairs regulatory T cells and unmasks AFP-specific CD4+ T-cell responses in patients with advanced HCC. J. Immunother.33(2),211–218 (2010).
