MICA immune complex formed with alpha 3 domain-specific antibody activates human NK cells in a Fc-dependent manner
Tóm tắt
One of the mechanisms by which tumors evade immune surveillance is through shedding of the major histocompatibility complex (MHC) class I chain-related protein A and B (MICA/B) from their cell surface. MICA/B are ligands for the activating receptor NKG2D on NK and CD8 T cells. This shedding reduces cell surface levels of MICA/B and impairs NKG2D recognition. Shed MICA/B can also mask NKG2D receptor and is thought to induce NKG2D internalization, further compromising immune surveillance by NK cells. We isolated human primary NK cells from normal donors and tested the suppressive activity of soluble recombinant MICA in vitro. Utilizing a panel of novel anti-MICA antibodies, we further examined the stimulatory activities of anti-MICA antibodies that reversed the suppressive effects of soluble MICA. We show that suppressive effects of soluble MICA (sMICA) on NK cell cytolytic activity was not due to the down-regulation of cell surface NKG2D. In the presence of an α3 domain-specific MICA antibody, which did not obstruct NKG2D binding, sMICA-mediated NK cell suppression was completely reversed. Reversal of NK cell inhibition by sMICA was mediated by immune complex formation that agonized NKG2D signaling. Furthermore, this restorative activity was dependent on antibody Fc effector function as the introduction of Fc mutations to abrogate Fc receptor binding failed to reverse sMICA-mediated NK cell suppression. Furthermore, MICA immune complexes preformed with an α3 domain-specific antibody (containing a wild-type Fc) induced IFN-γ and TNF-α secretion by NK cells in the absence of cancer cells, whereas MICA immune complexes preformed with the Fc effectorless antibody failed to induce IFN-γ and TNF-α secretion. Finally, we demonstrated that MICA immune complexes formed with the α3 domain-specific antibody activates NKG2D on NK cells leading to the release of IFN-γ. Our results demonstrate that an α3 domain-specific MICA antibody can circumvent sMICA-mediated suppression of NK cell cytolytic activity. Moreover, our data suggest that MICA immune complexes formed with α3-specific antibodies can activate NKG2D receptor and restore NK cell function in a Fc-dependent manner. The clinical utility of α3 domain-specific MICA/B antibodies may hold great promise as a new strategy for cancer immunotherapy.
Tài liệu tham khảo
Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol. 2001;1:41–9.
Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3:781–90.
Billadeau DD, Upshaw JL, Schoon RA, Dick CJ, Leibson PJ. NKG2D-DAP10 triggers human NK cell–mediated killing via a Syk-independent regulatory pathway. Nat Immunol. 2003;4:557–64.
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999;285:727–9.
Cosman D, Müllberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, et al. ULBPs, novel MHC class I–related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity. 2001;14:123–33.
Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK. Complex structure of the activating immunoreceptor NKG2D and its MHC class I–like ligand MICA. Nat Immunol. 2001;2:443–51.
Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol. 2001;2:255–60.
Groh V, Steinle A, Bauer S, Spies T. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science. 1998;279:1737–40.
Zhang J, Basher F, Wu JD. NKG2D ligands in tumor immunity: two sides of a coin. Front Immunol. 2015;6:97.
Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature. 2001;413:165–71.
Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008;28:571–80.
Salih HR, Rammensee H-G, Steinle A. Cutting edge: Down-regulation of MICA on human tumors by proteolytic shedding. J Immunol. 2002;169:4098–102.
Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR. Soluble MICA in malignant diseases. Int J Cancer. 2006;118:684–7.
Wu JD, Higgins LM, Steinle A, Cosman D, Haugk K, Plymate SR. Prevalent expression of the immunostimulatory MHC class I chain–related molecule is counteracted by shedding in prostate cancer. J Clin Invest. 2004;114:560–8.
Doubrovina ES, Doubrovin MM, Vider E, Sisson RB, O’Reilly RJ, Dupont B, et al. Evasion from NK cell immunity by MHC class I chain-related molecules expressing Colon adenocarcinoma. J Immunol. 2003;171:6891–9.
Märten A, von Lilienfeld-Toal M, Büchler MW, Schmidt J. Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing γδ T cell cytotoxicity. Int J Cancer. 2006;119:2359–65.
Jinushi M, Vanneman M, Munshi NC, Tai Y-T, Prabhala RH, Ritz J, et al. MHC class I chain-related protein a antibodies and shedding are associated with the progression of multiple myeloma. PNAS. 2008;105:1285–90.
Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002;419:734–8.
Jinushi M, Hodi FS, Dranoff G. Therapy-induced antibodies to MHC class I chain-related protein a antagonize immune suppression and stimulate antitumor cytotoxicity. PNAS. 2006;103:9190–5.
Zhang J, Liu D, Li G, Staveley-O’Carroll KF, Graff JN, Li Z, et al. Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy. Sci Adv. 2017;3:1–12.
Ferrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity. Science. 2018;359:1537–42.
Lombana TN, Matsumoto ML, III JB, Berkley AM, Toy E, Cook R, et al. High-resolution glycosylation site-engineering method identifies MICA epitope critical for shedding inhibition activity of anti-MICA antibodies. mAbs. 2019;11:75–93.
Gao X, Single RM, Karacki P, Marti D, O’Brien SJ, Carrington M. Diversity of MICA and Linkage disequilibrium with HLA-B in two north American populations. Hum Immunol. 2006;67:152–8.
Castriconi R, Cantoni C, Chiesa MD, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A. Transforming growth factor β1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. PNAS. 2003;100:4120–5.
Koch C, Kim Y, Zöller T, Born C, Steinle A. Chronic NKG2D engagement in vivo differentially impacts NK cell responsiveness by activating NK receptors. Front Immunol. 2017;8:1–11.
McFarland BJ, Kortemme T, Yu SF, Baker D, Strong RK. Symmetry recognizing asymmetry: analysis of the interactions between the C-type lectin-like Immunoreceptor NKG2D and MHC class I-like ligands. Structure. 2003;11:411–22.
Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science. 2006;311:1924–7.
Dubois S, Patel HJ, Zhang M, Waldmann TA. And mu¨ller JR. Preassociation of IL-15 with IL-15Rα-IgG1-fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J Immunol. 2008;180:2099–106.
Mistry AR, O’Callaghan CA. Regulation of ligands for the activating receptor NKG2D. Immunology. 2007;121:439–47.
Spear P, Wu M, Sentman M, Sentman CL. NKG2D ligands as therapeutic targets. Cancer Immun. 2013;13:1–14.
Brett K, Kaiser B, Yim, Ting Chow T, Gonzalez S, Dai Z, Mann HH, Strong RK, Groh V, Spies T. Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature. 2007;444:482–7.
Waldhauer I, Goehlsdorf D, Gieseke F, Weinschenk T, Wittenbrink M, Ludwig A, Stevanovic S, Rammensee SG, Steinle A. Tumor-associated MICA is shed by ADAM proteases. Cancer Res. 2008;68(15):6368–76.
Courau T, Bonnereau J, Chicoteau J, Bottois H, Remark R, Assante Miranda L, et al. Cocultures of human colorectal tumor spheroids with immune cells reveal the therapeutic potential of MICA/B and NKG2A targeting for cancer treatment. J ImmunoTherapy of Cancer. 2019;7:74–87.