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1.
Zhou J Yuen NK Zhan Q Velazquez EF Murphy GF Giobbie-Hurder A Hodi FS 《Cancer immunology, immunotherapy : CII》2012,61(5):655-665
Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families.
Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally
relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma,
contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune
responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by
immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein
was utilized to screen cellular responses in stage I–IV patients and healthy controls by ELISPOT. A broad array of CD4+ and CD8+ cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLA-A*0201 epitopes
were analyzed further for frequency of reactivity. The generation of specific CD4+ and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and
tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in
a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune
responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune
responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis
support the development of ML-IAP as a disease marker and therapeutic target. 相似文献
2.
Ladányi A 《Magyar onkologia》2003,47(1):113-117
Despite their well-documented immunogenicity, malignant melanomas belong to the most aggressive tumor types. A potential explanation for this is the suboptimal activation of tumor infiltrating T cells. In order to boost immune responses against tumors, a variety of treatment modalities have been tested in animal models and in clinical setting. Antigen-nonspecific approaches (e.g., IFN-alpha and IL-2), as well as active specific immunotherapeutical modalities based on the use of autologous or allogeneic tumor cell-save been investigated in clinical trials of melanoma. The identification of melanoma-associated antigens has opened new avenues in antigen-specific immunotherapy. A promising alternative for the delivery of different forms of melanoma antigens is the application of dendritic cells, the most potent antigen presenting cells capable of eliciting efficient T-cell response. Beside active immunotherapy, immune response against melanoma antigens could be increased through the adoptive transfer of tumor infiltrating lymphocytes or antigen specific T-cell clones. The most important conclusion that can be drawn from the results of published immunotherapy studies is that these modalities are able to induce durable complete tumor regressions,mostly with reasonable toxicity; however, generally only in a minority of patients. This points to the importance of appropriate patient selection, with regard to the expression of the targeted antigens and HLA molecules, as well as to the general immunocompetence of the patients. A crucial and still unsolved question is monitoring immune activation during treatment, although there are promising new tools that could prove useful in this respect. The presence of tumor-reactive CTL in the circulation or in the tumors does not guarantee an efficient immune response. It is important to assess if these T cells are in an activated and functional state. Finally, in several single target antigen-based clinical studies a therapy-induced immunoselection of antigen-negative clones, leading to disease progression, was observed. This could be overcome with the use of antigen cocktails or whole tumor approaches. A better understanding of the mechanisms of action of immunotherapeutical modalities may enhance the success rate of these strategies. 相似文献
3.
4.
ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas 总被引:106,自引:0,他引:106
BACKGROUND: Inhibitors of apoptosis (IAPs) are a family of cell death inhibitors found in viruses and metazoans. All IAPs have at least one baculovirus IAP repeat (BIR) motif that is essential for their anti-apoptotic activity. IAPs physically interact with a variety of pro-apoptotic proteins and inhibit apoptosis induced by diverse stimuli. This allows them to function as sensors and inhibitors of death signals that emanate from a variety of pathways. RESULTS: Here we report the characterization of ML-IAP, a novel human IAP that contains a single BIR and RING finger motif. ML-IAP is a powerful inhibitor of apoptosis induced by death receptors and chemotherapeutic agents, probably functioning as a direct inhibitor of downstream effector caspases. Modeling studies of the structure of the BIR domain revealed it to closely resemble the fold determined for the BIR2 domain of X-IAP. Deletion and mutational analysis demonstrated that integrity of the BIR domain was required for anti-apoptotic function. Tissue survey analysis showed expression in a number of embryonic tissues and tumor cell lines. In particular, the majority of melanoma cell lines expressed high levels of ML-IAP in contrast to primary melanocytes, which expressed undetectable levels. These melanoma cells were significantly more resistant to drug-induced apoptosis. CONCLUSIONS: ML-IAP, a novel human IAP, inhibits apoptosis induced by death receptors and chemotherapeutic agents. The BIR of ML-IAP possesses an evolutionarily conserved fold that is necessary for anti-apoptotic activity. Elevated expression of ML-IAP renders melanoma cells resistant to apoptotic stimuli and thereby potentially contributes to the pathogenesis of this malignancy. 相似文献
5.
Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient 总被引:2,自引:0,他引:2
Real LM Jimenez P Kirkin A Serrano A García A Cantón J Zeuthen J Garrido F Ruiz-Cabello F 《Cancer immunology, immunotherapy : CII》2001,49(11):621-628
Progressive tumor growth may be associated with suppression of the immune response. Many different mechanisms may contribute
to immune evasion. We investigated some of these mechanisms in melanoma cells lines generated from two patients. These cell
lines show a complex pattern of altered HLA expression; however, the resulting phenotype did not satisfactorily explain the
simultaneous evasion of T and NK cell cytotoxicity. Two additional alterations have now been detected in these melanoma cell
lines: (1) resistance to FAS-induced apoptosis caused by defective FAS gene expression, and (2) constitutive expression of
immunosuppressive cytokines. Our results show that several of the major mechanisms for immune evasion may coexist in a single
tumor. This suggests that tumor progression may give rise to an extremely resistant phenotype, which may be an impediment
to some immunotherapeutic strategies. We hypothesize that the simultaneous presence of several mechanisms involved in tumor
immune evasion must be the result of progressive selection of characteristics that are advantageous for tumor survival in
a competent host. Our findings do not support the possibility that FASL expression is a common mechanism of evasion of immune
response in melanoma cells.
Received: 27 January 2000 / Accepted: 28 August 2000 相似文献
6.
Redas Trepiakas Annika Berntsen Sine Reker Hadrup Jon Bjørn Poul F. Geertsen Per Thor Straten Mads H. Andersen Anders E. Pedersen Amir Soleimani Torben Lorentzen Julia S. Johansen Inge Marie Svane 《Cytotherapy》2010,12(6):721-734
Background aimsDendritic cells are regarded as the most effective antigen presenting cells and coordinators of the immune response and therefore suitable as vaccine basis. Here we present results from a clinical study in which patients with malignant melanoma (MM) with verified progressive disease received vaccination with autologous monocyte-derived mature dendritic cells (DC) pulsed with p53, survivin and telomerase-derived peptides (HLA-A2+ patients) or with autologous/allogeneic tumor lysate (HLA-A2? patients) in combination with low-dose interleukin (IL)-2 and interferon (IFN)-α2b.ResultsOf 46 patients who initiated treatment, 10 stopped treatment within 1–4 weeks because of rapid disease progression and deterioration. After 8 weeks, 36 patients were evaluable: no patient had an objective response, 11 patients had stable disease (SD); six had continued SD after 4 months, and three patients had prolonged SD for more than 6 months. The mean overall survival time was 9 months, with a significantly longer survival (18.4 months) of patients who attained SD compared with patients with progressive disease (PD) (5 months). Induction of antigen-specific T-cell responses was analyzed by multidimensional encoding of T cells using HLA-A2 major histocompatibility complex (MHC) multimers. Immune responses against five high-affinity vaccine peptides were detectable in the peripheral blood of six out of 10 analyzed HLA-A2+ patients. There was no observed correlation between the induction of immune responses and disease stabilization. A significant lower blood level of regulatory T cells (CD25high CD4 T cells) was demonstrable after six vaccinations in patients with SD compared with PD.ConclusionsVaccination was feasible and safe. Treatment-associated SD was observed in 24% of the patients. SD correlated with prolonged survival suggesting a clinical benefit. Differences in the level of regulatory T cells among SD and PD patients could indicate a significant role of these immune suppressive cells. 相似文献
7.
Alexei F. Kirkin P. thor Straten J. Zeuthen 《Cancer immunology, immunotherapy : CII》1996,42(4):203-212
Human melanoma is a highly immunogenic tumor capable of inducing a specific immune response. A number of melanoma-associated
antigens have been characterized during the past several years and can be classified into two groups: differentiation antigens
– present also in normal melanocytes – and tumor-specific antigens, which, with the exception of testis, are present only
in tumor cells. In a previous publication [Kirkin A. F., Petersen T. R., Olsen A. C., Li L., thor Straten P., Zeuthen J. (1995)
Cancer Immunol Immunother 41:71] we have described the production of clones of cytotoxic T lymphocytes (CTL) against the highly
immunogenic human melanoma cell line FM3. Using these clones we have defined four previously unknown melanoma-associated antigens,
which could be subdivided into differentiation and progression antigens. In the experiments reported in this paper, we have
further compared CTL clones from different groups and shown that the sensitivity of melanoma cells to CTL that recognize differentiation
or progression antigens is differentially modulated during tumor progression as well as by the lymphokines interferon γ (IFNγ)
and interleukin-10 (IL-10). The interaction of CTL clones recognizing progression antigens was strongly increased after treatment
of melanoma cells with IFNγ, while the recognition by CTL clones specific for differentiation antigens either was unchanged
or significantly decreased. IL-10 treatment of melanoma cells induced up-regulation with respect to recognition by CTL clones
specific for differentiation antigens without affecting the recognition of melanoma cells by CTL clones specific for progression
antigens. Using cellular systems at different stages of tumor progression, we demonstrated that the progressed state of melanoma
cells is associated with increased sensitivity to recognition by CTL clones detecting progression antigens, and with decreased
sensitivity to CTL clones recognizing differentiation antigens. Mimicking tumor progression, treatment with IFN-γ induced
apparent down-regulation of differentiation antigens. A hypothesis is suggested in which IFN-γ plays different roles in the
immune response against poorly immunogenic and highly immunogenic melanoma cells, increasing the progression of poorly immunogenic
tumor cells or promoting a strong immune response and regression of highly immunogenic melanoma cells.
Received: 23 November 1995 / Accepted: 7 March 1996 相似文献
8.
Varfolomeev E Moradi E Dynek JN Zha J Fedorova AV Deshayes K Fairbrother WJ Newton K Le Couter J Vucic D 《The Biochemical journal》2012,447(3):427-436
ML-IAP [melanoma IAP (inhibitor of apoptosis)] is an anti-apoptotic protein that is expressed highly in melanomas where it contributes to resistance to apoptotic stimuli. The anti-apoptotic activity and elevated expression of IAP family proteins in many human cancers makes IAP proteins attractive targets for inhibition by cancer therapeutics. Small-molecule IAP antagonists that bind with high affinities to select BIR (baculovirus IAP repeat) domains have been shown to stimulate auto-ubiquitination and rapid proteasomal degradation of c-IAP1 (cellular IAP1) and c-IAP2 (cellular IAP2). In the present paper, we report ML-IAP proteasomal degradation in response to bivalent, but not monovalent, IAP antagonists. This degradation required ML-IAP ubiquitin ligase activity and was independent of c-IAP1 or c-IAP2. Although ML-IAP is best characterized in melanoma cells, we show that ML-IAP expression in normal mammalian tissues is restricted largely to the eye, being most abundant in ciliary body epithelium and retinal pigment epithelium. Surprisingly, given this pattern of expression, gene-targeted mice lacking ML-IAP exhibited normal intraocular pressure as well as normal retinal structure and function. The results of the present study indicate that ML-IAP is dispensable for both normal mouse development and ocular homoeostasis. 相似文献
9.
Cabrera T Lara E Romero JM Maleno I Real LM Ruiz-Cabello F Valero P Camacho FM Garrido F 《Cancer immunology, immunotherapy : CII》2007,56(5):709-717
Our knowledge of the mechanisms underlying tumor-specific immune response and tumor escape has considerably increased. HLA class I antigen defects remain an important tumor escape mechanism since they influence the interactions between tumor cells and specific T and NK cells in the course of malignant disease. We have studied here HLA class I expression in six subcutaneous metastases obtained from a melanoma patient immunized with an autologous melanoma cell vaccine (M-VAX). We report in this paper that HLA class I antigen expression on these metastatic lesions strongly correlated with the course of the disease. The three metastases that were partially regressing at the time of their excision showed a strong HLA class I expression, whereas the progressing ones showed a very weak or negative staining with most of the anti-HLA class I mAbs used. Real-time quantitative PCR of the samples obtained from microdissected tumor tissue revealed a significant difference in the mRNA levels of HLA-ABC heavy chain and beta2m between the two types of metastases, i.e., lower levels in progressing metastases and high levels in regressing ones, confirming the immunohistological findings. This is, to our knowledge, the first report where the clinical outcome of different HLA class I positive and negative melanoma metastases can be clearly correlated with the regression and progression of the disease, respectively. 相似文献
10.
Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer 总被引:1,自引:0,他引:1
Williams BB Wall M Miao RY Williams B Bertoncello I Kershaw MH Mantamadiotis T Haber M Norris MD Gautam A Darcy PK Ramsay RG 《Cancer immunology, immunotherapy : CII》2008,57(11):1635-1645
Overexpression of the proto-oncogene c-Myb occurs in more than 80% of colorectal cancer (CRC) and is associated with aggressive disease and poor prognosis. To test c-Myb as a therapeutic target in CRC we devised a DNA fusion vaccine to generate an anti-CRC immune response. c-Myb, like many tumor antigens, is weakly immunogenic as it is a "self" antigen and subject to tolerance. To break tolerance, a DNA fusion vaccine was generated comprising wild-type c-Myb cDNA flanked by two potent Th epitopes derived from tetanus toxin. Vaccination was performed targeting a highly aggressive, weakly immunogenic, subcutaneous, syngeneic, colon adenocarcinoma cell line MC38 which highly expresses c-Myb. Prophylactic intravenous vaccination significantly suppressed tumor growth, through the induction of anti-tumor immunity for which the tetanus epitopes were essential. Vaccination generated anti-tumor immunity mediated by both CD4(+) and CD8(+) T cells and increased infiltration of immune effector cells at the tumor site. Importantly, no evidence of autoimmune pathology in endogenous c-Myb expressing tissues was detected as a consequence of breaking tolerance. In summary, these results establish c-Myb as a potential antigen for immune targeting in CRC and serve to provide proof of principle for the continuing development of DNA vaccines targeting c-Myb to bring this approach to the clinic. 相似文献
11.
Oberoi-Khanuja TK Karreman C Larisch S Rapp UR Rajalingam K 《The Journal of biological chemistry》2012,287(34):28445-28455
Inhibitor of apoptosis (IAPs) proteins are characterized by the presence of evolutionarily conserved baculoviral inhibitor of apoptosis repeat (BIR) domains, predominantly known for their role in inhibiting caspases and, thereby, apoptosis. We have shown previously that multi-BIR domain-containing IAPs, cellular IAPs, and X-linked IAP can control tumor cell migration by directly regulating the protein stability of C-RAF kinase. Here, we extend our observations to a single BIR domain containing IAP family member melanoma-IAP (ML-IAP). We show that ML-IAP can directly bind to C-RAF and that ML-IAP depletion leads to an increase in C-RAF protein levels, MAPK activation, and cell migration in melanoma cells. Thus, our results unveil a thus far unknown role for ML-IAP in controlling C-RAF stability and cell migration. 相似文献
12.
Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM Rommelfanger D Ilett E Pease L Pandha H Harrington K Selby P Melcher A Vile R 《Nature biotechnology》2012,30(4):337-343
Multiple intravenous injections of a cDNA library, derived from human melanoma cell lines and expressed using the highly immunogenic vector vesicular stomatitis virus (VSV), cured mice with established melanoma tumors. Successful tumor eradication was associated with the ability of mouse lymphoid cells to mount a tumor-specific CD4(+) interleukin (IL)-17 recall response in vitro. We used this characteristic IL-17 response to screen the VSV-cDNA library and identified three different VSV-cDNA virus clones that, when used in combination but not alone, achieved the same efficacy against tumors as the complete parental virus library. VSV-expressed cDNA libraries can therefore be used to identify tumor rejection antigens that can cooperate to induce anti-tumor responses. This technology should be applicable to antigen discovery for other cancers, as well as for other diseases in which immune reactivity against more than one target antigen contributes to disease pathology. 相似文献
13.
Sanaa El Marsafy Martine Bagot Armand Bensussan Alain Mauviel 《Pigment cell & melanoma research》2009,22(1):30-41
Melanoma is an aggressive malignancy with poor prognosis. Eradication of tumor cells requires an effective interaction between melanoma cells and different players of the immune system. As the most potent professional antigen‐presenting cells, dendritic cells (DCs) play a pivotal role in mounting a specific immune response where their intratumoral and peritumoral density as well as their functional status are correlated with clinical staging of the disease and with patients’ survival. Under steady‐state conditions, internalization of apoptotic cells by immature DCs designates a state of tolerance to self‐antigens. Nevertheless, pathogens and necrotic cells interacting with pattern recognition receptors trigger downstream signaling pathways that evoke maturation of DCs, leading to the production of pro‐inflammatory cytokines. These mature DCs are essential for T‐cell priming and subsequent development of a specific immune response. Altered functions of DCs have an impact on the development of various disorders including autoimmune diseases and cancers. Herein, we focus on the checkpoints created throughout DCs antigen capturing and presentation to T cells, with subsequent development of either tolerance or immune response, with an emphasis on the role played by DCs in melanoma tumorigenesis and their therapeutic potential. 相似文献
14.
Jürgen C. Becker Mads H. Andersen Valeska Hofmeister-Müller Marion Wobser Lidia Frey Christiane Sandig Steffen Walter Harpreet Singh-Jasuja Eckhart K?mpgen Andreas Opitz Marc Zapatka Eva-B. Br?cker Per thor Straten David Schrama Selma Ugurel 《Cancer immunology, immunotherapy : CII》2012,61(11):2091-2103
Background
Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets.Patients and methods
This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS).Results
Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR?+?PR?+?SD) more often showed SSTRs than patients with disease progression (p?=?0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6?months; p?=?0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p?=?0.013). The induction of SSTRs was associated with gender (female vs. male; p?=?0.014) and disease stage (M1a/b vs. M1c; p?=?0.010), but not with patient age, HLA type, performance status, or vaccination regimen.Conclusion
Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma. 相似文献15.
Goforth R Salem AK Zhu X Miles S Zhang XQ Lee JH Sandler AD 《Cancer immunology, immunotherapy : CII》2009,58(4):517-530
Anti-tumor vaccines capable of activating both CD4 and CD8 T cells are preferred for long lasting T cell responses. Induction
of a tumor-specific T-cell response can be induced by tumor vaccines that target innate immunity. The ensuing T-cell response
depends on efficient antigen presentation from phagocytosed cargo in the antigen presenting cell and is augmented by the presence
of Toll-like receptor (TLR) ligands within the cargo. Biodegradable polymers are useful for vaccine delivery in that they
are phagocytosed by antigen presenting cells (APCs) and could potentially be loaded with both the antigen and immune stimulatory
TLR agents. This study was undertaken to evaluate the effect of poly lactic-co-glycolic acid (PLGA) polymer particles loaded
with antigenic tumor lysate and immune stimulatory CpG oligonucleotides on induction of tumor specific immunity in a mouse
model of melanoma. We found that after delivery, these immune stimulatory antigen loaded particles (ISAPs) efficiently activated
APCs and were incorporated into lysosomal compartments of macrophages and dendritic cells. ISAP vaccination resulted in remarkable
T cell proliferation, but only modestly suppressed tumor growth of established melanoma. Due to this discordant effect on
tumor immunity we evaluated the role of regulatory T cells (Treg) and found that ISAP vaccination or tumor growth alone induced
prolific expansion of tumor specific Treg. When the Treg compartment was suppressed with anti-CD25 antibody, ISAP vaccination
induced complete antigen-specific immunity in a prophylactic model. ISAP vaccination is a novel tumor vaccine strategy that
is designed to co-load the antigen with a TLR agonist enabling efficient Ag presentation. Targeting of T-reg expansion during
vaccination may be necessary for inducing effective tumor-specific immunity.
Supported in part by grants from NIH R21 CA100652-01, the American Cancer Society IRG-77-004-28 and Michael C. Sandler. 相似文献
16.
Alexander AN Huelsmeyer MK Mitzey A Dubielzig RR Kurzman ID Macewen EG Vail DM 《Cancer immunology, immunotherapy : CII》2006,55(4):433-442
A xenogeneic melanoma-antigen-enhanced allogeneic tumor cell vaccine (ATCV) is an appealing strategy for anti-cancer immunotherapy
due to its relative ease of production, and the theoretical possibility that presentation of a multiplex of antigens along
with a xenogeneic antigen would result in cross-reaction between the xenogeneic homologs and self-molecules, breaking tolerance
and ultimately resulting in a clinically relevant immune response. In this study, we evaluated the efficacy of such a strategy
using a xenogeneic melanoma differentiation antigen, human glycoprotein 100 (hgp100) in the context of a phase II clinical
trial utilizing spontaneously arising melanoma in pet dogs. Our results demonstrate that the approach was well tolerated and
resulted in an overall response rate (complete and partial response) of 17% and a tumor control rate (complete and partial
response and stable disease of >6 weeks duration) of 35%. Dogs that had evidence of tumor control had significantly longer
survival times than dogs that did not experience control. Delayed type hypersensitivity (DTH) to 17CM98 canine melanoma cells
used in the whole cell vaccine was enhanced by ATCV and correlated with clinical response. In vitro cytotoxicity was enhanced
by ATCV, but did not correlate with clinical response. Additionally, anti-hgp100 antibodies were elicited in response to ATCV
in the majority of patients tested; however, this also did not correlate with clinical response. This approach, along with
further elucidation of the mechanisms of tumor protection after xenogeneic immunization, may allow the development of more
rational vaccines. This trial also further demonstrates the utility of spontaneous tumors in companion animals as a valid
translational model for the evaluation of novel vaccine therapies.
E.G. MacEwen deceased 相似文献
17.
18.
Tarazona R Casado JG Soto R DelaRosa O Peralbo E Rioja L Peña J Solana R 《Cancer immunology, immunotherapy : CII》2004,53(10):911-924
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. 相似文献
19.
The Calpain/Calpastatin System Has Opposing Roles in Growth and Metastatic Dissemination of Melanoma
Quentin Raimbourg Jo?lle Perez Sophie Vandermeersch Aurélie Prignon Guillaume Hanouna Jean-Philippe Haymann Laurent Baud Emmanuel Letavernier 《PloS one》2013,8(4)
Conventional calpains are ubiquitous cysteine proteases whose activity is promoted by calcium signaling and specifically limited by calpastatin. Calpain expression has been shown to be increased in human malignant cells, but the contribution of the calpain/calpastatin system in tumorigenesis remains unclear. It may play an important role in tumor cells themselves (cell growth, migration, and a contrario cell death) and/or in tumor niche (tissue infiltration by immune cells, neo-angiogenesis). In this study, we have used a mouse model of melanoma as a tool to gain further understanding of the role of calpains in tumor progression. To determine the respective importance of each target, we overexpressed calpastatin in tumor and/or host in isolation. Our data demonstrate that calpain inhibition in both tumor and host blunts tumor growth, while paradoxically increasing metastatic dissemination to regional lymph nodes. Specifically, calpain inhibition in melanoma cells limits tumor growth in vitro and in vivo but increases dissemination by amplifying cell resistance to apoptosis and accelerating migration process. Meanwhile, calpain inhibition restricted to host cells blunts tumor infiltration by immune cells and angiogenesis required for antitumor immunity, allowing tumor cells to escape tumor niche and disseminate. The development of highly specific calpain inhibitors with potential medical applications in cancer should take into account the opposing roles of the calpain/calpastatin system in initial tumor growth and subsequent metastatic dissemination. 相似文献
20.
In situ T cells in melanoma 总被引:3,自引:0,他引:3
Per thor Straten Jürgen C. Becker Per Guldberg Jesper Zeuthen 《Cancer immunology, immunotherapy : CII》1999,48(7):386-395
During the past decade new insights have been gained into the role of T lymphocytes in the host's immune response to cancer
in general and to melanoma in particular. Several melanoma-associated antigens (MAA) recognized by T cells have been characterized,
and a number of HLA class I- and class II-restricted peptides have been identified. These antigens can be divided into three
different groups: tumor-associated testis-specific antigens, melanocyte differentiation antigens, and mutated or aberrantly
expressed antigens. These proteins give rise to several antigenic peptides. The number of known melanoma-associated peptides
that can induce killing by cytotoxic T-lymphocytes (CTL) exceeds 30 and is still increasing. In line with these findings,
clinical data indicate that the immune system is essential in the control of tumor growth. A brisk infiltration of lymphocytes
is associated with a favorable prognosis, and complete or partial regression of primary melanoma occurs quite frequently.
Furthermore, immunomodulatory therapies have accomplished complete or partial tumor regression in a number of patients. However,
the immune response is in most cases inadequate to control tumor growth as tumor progression often occurs. Hence, the coexistence
of a cellular immune response in melanoma lesions, demonstrated by the presence of clonally expanded T cells, remains a major
paradox of tumor immunology. In the present paper we review current knowledge regarding tumor infiltrating lymphocytes (TIL)
in melanoma and discuss possible mechanisms of escape from immune surveillance.
Received: 20 March 1999 / Accepted: 3 March 1999 相似文献