Lymphocyte activation in response to melanoma: interaction of NK-associated receptors and their ligands (original) (raw)
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Expression of NK-associated receptors on cytotoxic T cells from melanoma patients: a two-edged sword
Cancer Immunology Immunotherapy, 2004
The coexistence of tumor progression with a tumor-specific immune response constitutes a major paradox of tumor immunity. During the last decade, the presence of cytotoxic T lymphocytes (CTLs) recognising melanoma-associated antigens has been unequivocally demonstrated in numerous different in vivo and in vitro models. However, most often these melanoma-specific T lymphocytes do not control tumor growth. Several mechanisms that involve changes in melanoma phenotype and/or in T-cell differentiation and function could explain the inability of the immune response to control melanoma. In the last few years it has been demonstrated that cellular cytotoxicity is the result of a balance between activating signals triggered by the TCR and costimulatory molecules and inhibitory signals triggered by inhibitory receptors expressed by the CTL. Because the final outcome of the immune response against melanoma depends on the balance between activating and inhibitory signals, the expression de novo on melanoma cells of ligands for inhibitory NKRs and the down-regulation of costimulatory molecules may favor the escape of tumor cells from immunosurveillance. In this paper we review how altered expression of molecules required for T-cell costimulation could result in impaired lysis of melanoma. The modulation of antimelanoma T-cell responses by a group of receptors originally described on NK cells (NK-associated receptors) but which are now known also to be expressed on a subset of cytolytic effector cells is reviewed. We hypothesize that the expression of ligands for NKRs on melanoma cells may contribute to T-cell-mediated immune responses against melanoma either enhancing or inhibiting activation and differentiation to effector cells. Blocking inhibitory receptors or increasing activating receptors could result in new strategies to improve T-cell-mediated rejection of melanoma.
Journal of Experimental Medicine, 1999
Natural killer (NK) receptor signaling can lead to reduced cytotoxicity by NK cells and cytolytic T lymphocytes (CTLs) in vitro. Whether T cells are inhibited in vivo remains unknown, since peptide antigen-specific CD8 ϩ T cells have so far not been found to express NK receptors in vivo. Here we demonstrate that melanoma patients may bear tumor-specific CTLs expressing NK receptors. The lysis of melanoma cells by patient-derived CTLs was inhibited by the NK receptor CD94/NKG2A. Thus, tumor-specific CTL activity may be decreased through NK receptor triggering in vivo.
Cancer Research, 2012
Natural killer (NK) cells play a key role in tumor immune surveillance. However, adoptive immunotherapy protocols using NK cells have shown limited clinical efficacy to date, possibly due to tumor escape mechanisms that inhibit NK cell function. In this study, we analyzed the effect of coculturing melanoma cells and NK cells on their phenotype and function. We found that melanoma cells inhibited the expression of major NK receptors that trigger their immune function, including NKp30, NKp44, and NKG2D, with consequent impairment of NK cellmediated cytolytic activity against various melanoma cell lines. This inhibitory effect was primarily mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2). Together, our findings suggest that immunosuppressive barriers erected by tumors greatly hamper the antitumor activity of human NK cells, thereby favoring tumor outgrowth and progression. Cancer Res; 72(6); 1407-15. Ó2012 AACR.
Cancer Immunology Immunotherapy, 2005
CD8+ T cells can express NK-associated receptors (NKRs) that may regulate their cytolytic function. We have characterized the expression of several NKRs on peripheral blood CD8+ T cells from melanoma patients and compared them to age-matched healthy donors. The analysis performed includes HLA class I specific receptors (KIRs, LILRB1 and CD94/NKG2) and other NK receptors like CD57, CD56 and CD16. Melanoma patients showed a higher variability in the expression of NKRs on circulating CD8+ T cells than age-matched healthy donors. NKR expression on CD8+ T cells from melanoma patients showed a significant increase of KIR2DL2/L3/S2 (mAb gl183), CD244, CD57, CD56 and CD16. We have also found an increase of CD8+ CD28− CD27− T cells in melanoma patients. This subset represents terminally differentiated effector cells expressing CD244 and high levels of perforin. The expression of NKRs was also mainly restricted to this T cell subset. Altogether, circulating CD8+ T cells from melanoma patients display a distinct phenotype characterized by downregulation of costimulatory molecules and higher expression of NKRs. We suggest that the increased expression of NKRs on T cells may contribute to the final outcome of the immune response against melanoma both stimulating or inhibiting activation and differentiation to effector cells. Blocking inhibitory receptor function and enhancing activating receptors may represent new strategies with therapeutic potential against melanoma.
Clinical Cancer Research, 2006
Because immune mechanisms involved in cutaneous melanoma have not been fully elucidated, efforts have been made to achieve prognosis markers and potential targets for immune therapies, but they have not been entirely fruitful thus far. Therefore, the goal of this study was to investigate the involvement of early changes in CD8 T cells and CD56 natural killer (NK) cells expressing NK receptors in different HLA-C dimorphism groups of melanoma patients. Experimental Design: CD8 T cells and CD56 NK cells were analyzed in 41 patients and 39 sex-and age-matched controls with different HLA-C genotypes by flow cytometry. HLA-C dimorphism at position 80 was tested by PCR sequence-specific primers and PCR sequencespecific oligonucleotide to examine whether it could mediate in the emergence of cells expressing killer cell immunoglobulin-like receptors. Results: Thirty-five of 41 patients had benign sentinel node, and showed an imbalance in the absolute number of CD8 + DR + or CD8 + CD161 + peripheral blood T cells according to the CD28 coexpression compared with controls. CD8 + CD28 À CD158a + T and CD56 + CD158a + NK cells were significantly increased in HLA-C Lys80 homozygous nonmetastatic patients, whereas only CD56 + CD158a + NK cells increased in heterozygous ones. An up-regulation of the CD158a KIR receptor was also seen on NK cells but not inTcells of patients at advanced disease stages. Conclusions:This work provides, for the first time, evidence of immune activation in early stages of cutaneous melanoma, together with an increase of cells expressing CD158a in patients bearing the corresponding HL A-C ligand, which may be important to evaluate the disease progression and to use individualized immune therapeutic approaches. Cutaneous melanoma is a malignant neoplasm of melanocytes characterized by an often undesirable clinical outcome. Although at present, early detection and surgery offer a high cure rate (1), this tumor can be elusive for the host immune surveillance, especially if a state of tolerance against tumor is induced (2, 3). Nonetheless, cutaneous malignant melanoma is considered one of the most immunogenic tumors (3-5). From this standpoint, and because the immune response against melanoma is not well established, several studies have been aimed at trying to clarify these mechanisms and to search for markers with predictive value in prognosis (6-9). Despite all these studies, potential targets for effective adjunctive therapies remain still undefined. CD8 T-lymphocytes and natural killer (NK) cells are believed to be important effector cells involved in eliciting a protection against melanoma (10-12). NK cytotoxic activity is regulated by the balance between activating and inhibitory signals, which are mediated by a group of receptors originally described on NK cells (13, 14), but also detected in minor peripheral blood T-cell subsets, mostly of the CD8 + CD28 À TCRah + phenotype (15, 16). NK-associated receptors (NKR) include non-HLA class Ispecific receptors, such as CD56, CD57, or CD161 (17-20), as well as receptors that recognize HLA class I molecules, such as CD94/NKG2 heterodimers belonging to the C-type lectin receptor family (21, 22), and killer receptors belonging to the immunoglobulin family (KIR), among them KIR2DL1/S1 and KIR2DL2/3/S2 (23-26). CD94/NKG2 receptors bind the nonclassic HLA-E molecules (27) and have a limited polymorphism. On the contrary, KIRs and their corresponding ligands in the HLA-C and HLA-B loci (21, 24) are highly polymorphic, conferring to KIR and HLA class I molecules a considerable potential as markers of disease susceptibility and progression (28). In the last years, much attention has been focused on the study of HLA-C, whose
Natural Killer Cell Recognition of Melanoma: New Clues for a More Effective Immunotherapy
Frontiers in Immunology, 2016
Natural killer (NK) cells participate in the early immune response against melanoma and also contribute to the development of an adequate adaptive immune response by their crosstalk with dendritic cells and cytokine secretion. Melanoma resistance to conventional therapies together with its high immunogenicity justifies the development of novel therapies aimed to stimulate effective immune responses against melanoma. However, melanoma cells frequently escape to CD8 T cell recognition by the down-regulation of major histocompatibility complex (MHC) class I molecules. In this scenario, NK cells emerge as potential candidates for melanoma immunotherapy due to their capacity to recognize and destroy melanoma cells expressing low levels of MHC class I molecules. In addition, the possibility to combine immune checkpoint blockade with other NK cell potentiating strategies (e.g., cytokine induction of activating receptors) has opened new perspectives in the potential use of adoptive NK cell-based immunotherapy in melanoma.
European Journal of Immunology, 2012
During the past few years, a number of studies reported that different melanoma cell lines could be extensively lysed in vitro by IL-2-activated NK cells at appropriate effector/target ratios. Here, we show, by histological evaluation of different melanoma lesions, that NK/target-cell ratios compatible with those allowing efficient melanoma cell killing in vitro are hardly reached at the tumor site. We then investigated the outcome of cocultures established at low NK/melanoma cell ratios. After initial NK-mediated lysis, residual melanoma cells acquired resistance to IL-2-activated NK cells. This reflected primarily an increased expression, on melanoma cells, of classical and nonclassical HLA class I molecules, accompanied by a partial downregulation of NKG2D-ligands, and was dependent on NK-mediated IFN-γ release. Consistently, melanoma lesions showed a higher HLA class I expression on tumor cells that were proximal to infiltrating NK cells. In long-term cocultures, the "protective phenotype" acquired by melanoma cells was lost over time. However, this phenomenon was counteracted by downregulation of relevant activating receptors in cocultured NK cells. Analysis of different NK-cell-activating cytokines indicated that IL-15 can partially overcome this novel tumor escape mechanism suggesting that IL-15, rather than IL-2, may be eligible for NK-cell-based immunotherapy.