[en] Recent studies demonstrated that autophagy is an important regulator of innate immune response. However, the mechanism by which autophagy regulates natural killer (NK) cell-mediated antitumor immune responses remains elusive. Here, we demonstrate that hypoxia impairs breast cancer cell susceptibility to NK-mediated lysis in vitro via the activation of autophagy. This impairment was not related to a defect in target cell recognition by NK cells but to the degradation of NK-derived granzyme B in autophagosomes of hypoxic cells. Inhibition of autophagy by targeting beclin1 (BECN1) restored granzyme B levels in hypoxic cells in vitro and induced tumor regression in vivo by facilitating NK-mediated tumor cell killing. Together, our data highlight autophagy as a mechanism underlying the resistance of hypoxic tumor cells to NK-mediated lysis. The work presented here provides a cutting-edge advance in our understanding of the mechanism by which hypoxia-induced autophagy impairs NK-mediated lysis in vitro and paves the way for the formulation of more effective NK cell-based antitumor therapies.
Disciplines :
Oncology
Author, co-author :
BAGINSKA, Joanna ; Laboratory of Experimental Hemato-Oncology, Department of Oncology, and Laboratory of Immunogenetics and Allergology, Public Research Center for Health, L-1526 Luxembourg City, Luxembourg.
VIRY, Elodie ; Laboratory of Experimental Hemato-Oncology, Department of Oncology
Zitvogel L, Tesniere A, Kroemer G (2006) Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 6(10):715-727.
Whiteside TL (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27(45):5904-5912.
Swartz MA, et al. (2012) Tumor microenvironment complexity: Emerging roles in cancer therapy. Cancer Res 72(10):2473-2480.
Smyth MJ, Hayakawa Y, Takeda K, Yagita H (2002) New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2(11):850-861.
Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107(1):159-166.
Smyth MJ, et al. (2000) Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 191(4):661-668.
Lv L, et al. (2011) The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma. PLoS ONE 6(3):e18219.
van Herpen CM, et al. (2005) Intratumoral recombinant human interleukin-12 administration in head and neck squamous cell carcinoma patients modifies locoregional lymph node architecture and induces natural killer cell infiltration in the primary tumor. Clin Cancer Res 11(5):1899-1909.
Ishigami S, et al. (2000) Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88(3):577-583.
Ménard C, et al. (2009) Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res 69(8):3563-3569.
Stanietsky N, Mandelboim O (2010) Paired NK cell receptors controlling NK cytotoxicity. FEBS Lett 584(24):4895-4900.
Stern-Ginossar N, Mandelboim O (2009) An integrated view of the regulation of NKG2D ligands. Immunology 128(1):1-6.
Kärre K, Ljunggren HG, Piontek G, Kiessling R (2005) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. 1986. J Immunol 174(11):6566-6569.
Campoli M, Ferrone S (2008) Tumor escape mechanisms: Potential role of soluble HLA antigens and NK cells activating ligands. Tissue Antigens 72(4):321-334.
Lee CT, Mace T, Repasky EA (2010) Hypoxia-driven immunosuppression: A new reason to use thermal therapy in the treatment of cancer? Int J Hyperthermia 26(3):232-246.
Noman MZ, et al. (2011) Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression. Cancer Res 71(18):5976-5986.
Bosco MC, Varesio L (2012) Dendritic cell reprogramming by the hypoxic environment. Immunobiology 217(12):1241-1249.
Youssef MM, Symonds P, Ellis IO, Murray JC (2006) EMAP-II-dependent lymphocyte killing is associated with hypoxia in colorectal cancer. Br J Cancer 95(6):735-743.
Chouaib S, et al. (2012) Hypoxia promotes tumor growth in linking angiogenesis to immune escape. Front Immunol 3:21.
Grimshaw MJ, Naylor S, Balkwill FR (2002) Endothelin-2 is a hypoxia-induced autocrine survival factor for breast tumor cells. Mol Cancer Ther 1(14):1273-1281.
Sceneay J, et al. (2012) Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res 72(16):3906-3911.
Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P (2010) The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol 10(8):554-567.
Siemens DR, et al. (2008) Hypoxia increases tumor cell shedding of MHC class I chainrelated molecule: Role of nitric oxide. Cancer Res 68(12):4746-4753.
Noman MZ, Janji B, Berchem G, Mami-Chouaib F, Chouaib S (2012) Hypoxia-induced autophagy: A new player in cancer immunotherapy? Autophagy 8(4):704-706.
Michaud M, et al. (2011) Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334(6062):1573-1577.
Heppner GH, Miller FR, Shekhar PM (2000) Nontransgenic models of breast cancer. Breast Cancer Res 2(5):331-334.
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: The next generation. Cell 144(5):646-674.
Ljunggren HG, Malmberg KJ (2007) Prospects for the use of NK cells in immunotherapy of human cancer. Nat Rev Immunol 7(5):329-339.
Wildenberg ME, et al. (2012) Autophagy attenuates the adaptive immune response by destabilizing the immunologic synapse. Gastroenterology 142(7):1493-1503.
Wowk ME, Trapani JA (2004) Cytotoxic activity of the lymphocyte toxin granzme B. Microbes Infect 6(8):752-758.
Gross C, Koelch W, DeMaio A, Arispe N, Multhoff G (2003) Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. J Biol Chem 278(42):41173-41181.
Lopez JA, Brennan AJ, Whisstock JC, Voskoboinik I, Trapani JA (2012) Protecting a serial killer: Pathways for perforin trafficking and self-defence ensure sequential target cell death. Trends Immunol 33(8):406-412.
Thiery J, et al. (2011) Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells. Nat Immunol 12(8): 770-777.
Longatti A, Tooze SA (2012) Recycling endosomes contribute to autophagosome formation. Autophagy 8(11):1682-1683.
Ciccone E, et al. (1995) General role of HLA class I molecules in the protection of target cells from lysis by natural killer cells: evidence that the free heavy chains of class I molecules are not sufficient to mediate the protective effect. Int Immunol 7(3): 393-400.
