Page 13 - Read Online

Feun et al. Immunotherapy for hepatocellular carcinoma

the blocking of TGF-β signaling in T-cells or deletion Schemmer P, Bruns H, Eiermann T, Price DA, Blum HE, Neumann-
of TGF-β from T-cells resulted in decreased PD-1 Haefelin C, Thimme R. Immunodominance and functional alterations
expression in tumor-infiltrating CD8+ T-cells. [56] Further of tumor-associated antigen-specific CD8+ T-cell responses in
studies in mice model of HCC showed that TGF-β 5. hepatocellular carcinoma. Hepatology 2014;59:1415-26.
Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF,
increased the PD-L1 expression in dendritic cells Korangy F. Increased populations of regulatory T cells in peripheral
which led to T-cell apoptosis and increased number blood of patients with hepatocellular carcinoma. Cancer Res
of CD25+, Foxp3+ T regulatory cells. [56,57] Thus, 2005;65:2457-64.
there is a strong rationale to target two pathways of 6. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW,
immunosuppression in HCC simultaneously. Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is
associated with prognosis of hepatocellular carcinoma after resection.
In summary, immunotherapy represents a novel 7. J Clin Oncol 2007;25:2586-93.
Zerbini A, Pilli M, Penna A, Pelosi G, Schianchi C, Molinari
approach to treat advanced hepatocellular carcinoma. A, Schivazappa S, Zibera C, Fagnoni FF, Ferrari C, Missale G.
Immune cells have been found in HCC specimens Radiofrequency thermal ablation of hepatocellular carcinoma liver
that appear “fatigued” or suppressed. New checkpoint nodules can activate and enhance tumor-specific T-cell responses.
inhibitors and other agents may awaken these Cancer Res 2006;66:1139-46.
immune cells to attack the tumor. Early results 8. Wissniowski TT, Hänsler J, Neureiter D, Frieser M, Schaber S,
from clinical trials suggest it is feasible to do so Esslinger B, Voll R, Strobel D, Hahn EG, Schuppan D. Activation of
and encouraging antitumor responses were been tumor-specific T lymphocytes by radiofrequency ablation of the VX2
hepatoma in rabbits. Cancer Res 2003;63:6496-500.
observed. The challenge is to further define what 9. Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K, Yamashita T,
patients may benefit from this approach, how to Nakamoto Y, Kaneko S. Increase in CD14+HLA-DR -/low myeloid-
predict or reduce toxicities, particularly liver toxicity, derived suppressor cells in hepatocellular carcinoma patients and its
and how best to combine this therapy with other impact on prognosis. Cancer Immunol Immunother 2013;62:1421-
known modalities of treatment. 30.
10. Ilkovitch D, Lopez DM. The liver is a site for tumor-induced
Authors’ contributions myeloid-derived suppressor cell accumulation and immuno-
suppression. Cancer Res 2009;69:5514-21.
Manuscript writing and editing: L.G. Feun 11. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns
Manuscript review, participating in the phase II MP, Greten TF, Korangy F. A new population of myeloid-derived
trial of Pembrolizumab in HCC, and performing the suppressor cells in hepatocellular carcinoma patients induces CD4(+)
CD25(+)Foxp3(+) T cells. Gastroenterology 2008;135:234-43.
laboratory correlates: Y.Y. Li, M. Wangpaichitr, C.J. 12. Greten TF, Ormandy LA, Fikuart A, Hochst B, Henschen S, Horning
Wu, N. Savaraj M, Manns MP, Korangy F. Low-dose cyclophosphamide treatment
impairs regulatory T cells and unmasks AFP-specific CD4+
Financial support and sponsorship T-cell responses in patients with advanced HCC. J Immunother
None. 2010;33:211-8.
13. Han Y, Chen Z, Yang Y, Jiang Z, Gu Y, Liu Y, Lin C, Pan Z, Yu
Conflicts of interest Y, Jiang M, Zhou W, Cao X. Human CD14+CTLA4+ regulatory
dendritic cells suppress T-cell response by cytotoxic T-lymphocyte
There are no conflicts of interest. antigen-4-dependent IL-10 and indoleamine-2-3-dioxgenase
production in hepatocellular carcinoma. Hepatology 2014;59:567-79.
Patient consent 14. Han Y, Yang Y, Chen Z, Jiang Z, Gu Y, Liu Y, Xu S, Lin C, Pan
Z, Zhou W, Cao X. Human hepatocellular carcinoma-infiltrating
There is no patient involved. CD4 CD69 Foxp3 regulatory T cell suppresses T cell response via
+
-
+
membrane-bound TGF-β1. J Mol Med (Berl) 2014;92:539-50.
Ethics approval 15. Kurokohchi K, Carrington M, Mann DL, Simonis TB, Alexander-
This review paper is waived for ethics approval. Miller MA, Feinstone SM, Akatsuka T, Berzofsky JA. Expression
of HLA class I molecules and the transporter associated with antigen
processing in hepatocellular carcinoma. Hepatology 1996;23:1181-8.
REFERENCES 16. Matsui M, Machida S, Itani-Yohda T, Akatsuka T. Downregulation
of the proteasome subunits, transporter, and antigen presentation in
1. Huz JI, Melis M, Sarpel U. Spontaneous regression of hepatocellular hepatocellular carcinoma, and their restoration by interferon-gamma.
carcinoma is most often associated with tumor hypoxia or a systemic J Gastroenterol Hepatol 2002;17:897-907.
inflammatory response. HPB (Oxford) 2012;14:500-5. 17. Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS,
2. Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Coleman N, Alexander GJ. Compromised lymphocytes infiltrate
Manns MP, Greten TF. Spontaneous tumor-specific humoral hepatocellular carcinoma: the role of T regulatory cells. Hepatology
and cellular immune responses to NY-ESO-1 in hepatocellular 2005;41:722-30.
carcinoma. Clin Cancer Res 2004;10:4332-41. 18. Cariani E, Pilli M, Zerbini A, Rota C, Olivani A, Pelosi G, Schianchi
3. Hato T, Goyal L, Greten TF, Duda DG, Zhu AX. Immune checkpoint C, Soliani P, Campanini N, Silini EM, Trenti T, Ferrari C, Missale
blockade in hepatocellular carcinoma: current progress and future G. Immunological and molecular correlates of disease recurrence
directions. Hepatology 2014;60:1776-82. after liver resection for hepatocellular carcinoma. PLos One
4. Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, 2012:7:es32493.
Hepatoma Research ¦ Volume 3 ¦ March 22, 2017 49