Potential Effects of Released Classical and Non Classical HLA Class I Antigens and NKCell Activating Ligands in the Tumor Microenvironment

Classical and non-classical HLA class I antigens as well as NK-cell activating lig-ands are expressed not only on cell membranes, but also in plasma [4, 41-43]. Classical HLA class I antigens are expressed as soluble molecules or bound to membranous nanoparticles or microvesicles [28] (Fig. 2.4). Whether HLA-G and NK-cell activating ligands are also bound to microvesicles is not known. Distinct mechanisms underlie their release from cells. They include secretion, proteolytic cleavage and metalloprotease-mediated cleavage of membrane bound molecules and alternative splicing. As a result different isoforms of classical and non-classical HLA class I antigens are present in plasma [41-43]. In view of the frequent loss of P2 m by malignant cells, it is noteworthy that both classical and non-classical HLA class I antigens have been detected in plasma not only as HLA class I heavy chain-P2 m-peptide complexes, but also as P2 m-free heavy chains. The latter maintain most, if not all the functional activities of P2 m-associated HLA class I heavy chains [41-43].

The functional role of soluble classical and non-classical HLA class I antigens as well as NK-cell activating ligands is not known. It is likely that they play a role in immunological phenomena, since they are immunologically active, as indicated by their reactivity with antibodies and/or with T cell receptors as well as by their immunogenicity in autologous, allogeneic and xenogeneic combinations [2, 27]. Furthermore, as already mentioned, the serum levels of classical and non-classical HLA class I antigens and of NK-cell activating ligands change in some pathological conditions; in some diseases these changes are associated with the clinical

Fig. 2.4 HLA class I and class II antigen expression on microvesicles isolated from sera of (pt) patients with head and neck cancer (HNC) or melanoma (mel) or from superna-tants of the SCCHN cell line PCI-13, of the melanoma cell lines mel 1 and mel 2, of the ovarian carcinoma cell line OVCa and of human dendritic cells (DC). Western blot analysis was performed with the HLA class I heavy chain-specific mAb HC-10 and with the HLA class II Bchain-specific mAb LGII-612.14

HNC melanoma

HNC melanoma

course of the disease [2, 4, 24, 25, 41]. However, to the best of our knowledge, in no case a cause-effect relationship between these two phenomena has been described.

Convincing evidence indicates that classical HLA class I antigens can induce apoptosis of activated CD8 T cells in vitro utilizing Fas-Fas ligand interactions [44, 63]. A similar result has been obtained for the non-classical HLA class I antigens HLA-G by Fournel et al. [10] and by us [6], although this finding has not been confirmed by Hunt [26] who has used recombinant HLA-G in her experiments. There is conflicting information about the mechanisms underlying the induction of apoptosis of activated T cells. The series of reactions leading to apoptosis of activated T cells is triggered by the interaction of HLA class I antigens with T cell receptors (TCR), according to Zavazava and Kronke [62], but with CD8 according to our own data [6, 44]. Furthermore there are conflicting data about the potency of classical and non-classical HLA class I antigens in inducing apoptosis of activated T cells. According to Fournel et al. [10] non-classical HLA class I antigens are more potent than classical HLA class I antigens, while the reverse is true according to our own data [6]. At any rate HLA class I antigens released from tumor cells in their microenvironment provide a mechanism for the presence of apoptotic T cells in the tumor microenvironment [58].

NK-cell activating ligands are also released from tumor cells by the activity of metalloproteases [21, 50, 57]. This causes not only downregulation of their expression on tumor cell membrane, but also promotes a reversible downregulation of NKG2D on NK and CD8 T cells because of its internalization [21, 50]. These changes have a negative impact on the immunosurveillance mediated by cytotoxic cells. Specifically the reduced expression of NK-cell activating ligands decreases the immunogenicity of tumor cells which is influenced by the density of NK-cell activating ligands on cell membrane. Furthermore the reduced surface NKGD2 expression impairs the cytotoxic activity of tumor antigen-specific CTL and of NK cells [21]. The causal role played by soluble NK-cell activating ligands in these phenomena is indicated by the results recently published by Dranoff and his collaborators [27]. The development of MICA-specific antibodies in patients treated with anti-CTLA-4 monoclonal antibodies or immunized with autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor was associated with a decrease in the levels of soluble MICA in serum and an increase in the expression of NKG2D on NK cells and CD8+ T cells and their cytotoxicity.

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