Direct evidence to support the immunosurveillance concept in a human regressive melanoma.

Mackensen, Andréas; Carcelain, Guislaine; Viel, Sophie; Raynal, Mathieu; Michalaki, H.; Triebel, Frédéric; Bosq, Jacques; Hercend, Thierry

doi:10.1172/jci117116

Cited by 155 publications

(89 citation statements)

References 26 publications

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“…CD8 1 T cells (5 3 10 4 cells/well) were cocultured with 2.5 3 10 4 peptide-pulsed autologous DCs per well (96 well round-bottom plates and 200 ll complete medium with 10% human AB serum and 1-2% T-cell growth factor (TCGF). 51 Medium was changed twice a week, and T cells were restimulated after 7 days with fresh peptide-pulsed DCs. After each stimulation, cell numbers were calculated by counting trypan-blue-negative cells.…”

Section: In Vitro Generation Of Autologous DCmentioning

confidence: 99%

“…44 CD4 1 p53 TCRtg or CD8 1 p53 TCRtg T cells (2 3 10 5 ) were cocultured for 48 hr with 2 3 10 5 peptide-loaded iDCs or mDCs, with the p53-expressing RCC cell line MZ1851RC or HLA-deficient K562 cells, in the absence of cytokines. The IFN-g Elispot (Diaclone, Besancon, France) and 51 Chromium-release-assay was performed in duplicate wells as reported. 52 Cytokine content in 48 hr supernatants (TNF-a, IFN-g, IL-2 and IL-4) was determined using ELISA according to standard protocols, using the afore-mentioned capture and detector antibodies.…”

Section: Coculture Of P53 Tcrtg T Cells With Dcs and Tumor Cellsmentioning

confidence: 99%

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Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses in vitro

Blank

Kuball

Voelkl

et al. 2006

Intl Journal of Cancer

271

201

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Human tumors frequently escape immune destruction, despite the presence of cyototoxic T cells (CTL) recognizing tumor-associated antigens (TAA). We have previously shown that programmed death ligand-1 (PD-L1), a recently identified ligand of the B7 superfamily, is expressed on murine tumors and can inhibit antitumor immune responses. To evaluate the clinical relevance of our animal model findings, we examined human tumors and tumorspecific T cells. We found PD-L1 to be constitutively expressed on human renal cell carcinoma (RCC) cell lines and upregulated on human melanoma cell lines upon exposure to interferon-gamma. Similarly, we found binding of anti-PD-L1 monoclonal antibody (mAb) on frozen sections from RCC and melanomas, but not on normal tissues. The corresponding inhibitory receptor of PD-L1, PD-1, revealed a higher expression on tumor-infiltrating lymphocytes than on peripheral blood lymphocytes (PBL) from melanoma patients upon specific antigen stimulation. Stimulation of PBL from healthy donors with peptide-loaded dendritic cells in the presence of anti-PD-L1 mAb altered neither the total T cell numbers after expansion, nor the percentage of peptide-specific CTL, when providing a T cell help by addition of cytokines. However, when stimulating TAA-specific CTL and T helper cells with Ag-pulsed dendritic cells in the absence of exogenous cytokines, PD-L1 blockade increased the cytokine production. Similar to the data achieved in the murine system, the blockade of PD-L1 on human tumors resulted in enhanced cytolytic activity of TAA-specific CTLs and cytokine production of TAA-specific T helper cells when interacting directly with the tumor. In summary, our data suggest that PD-L1/PD-1 interactions negatively regulate T cell effector functions predominately in the absence of exogenous cytokine support, indicating an important role for this pathway in tumor evasion. ' 2006 Wiley-Liss, Inc.Key words: RCC; PD-L1; PD-1; B7-H1; melanoma Although the prognosis for patients with advanced solid tumors still remains poor, 1 a number of promising approaches, such as cancer immunotherapy, have been developed over the past decade. However, it is still an unsolved question why existing tumor-specific T cells in cancer patients fail to effectively prevent tumor progression. Inefficient T cell stimulation, either due to the absence of efficient antigen-presentation and costimulation or due to the presence of coinhibitory molecules, may contribute to this phenomenon.Data from animal models showing that CD8 1 T cells can lead to regression and rejection of solid tumors, and metastases 2 were reproduced with human cancer patients in clinical studies only partially. [3][4][5][6] Despite the fact that tumor-specific T cells can be expanded and transferred effectively and thus survive and localize into tumors, 7,8 tumor growth is not always controlled.It appears that the microenvironment of cancers protects tumor cells from immune destruction. 9,10 Increasing appreciation of costimulation (via CD28 or ICOS) and coinhibition (...

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Section: In Vitro Generation Of Autologous DCmentioning

confidence: 99%

Section: Coculture Of P53 Tcrtg T Cells With Dcs and Tumor Cellsmentioning

confidence: 99%

Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses in vitro

Blank

Kuball

Voelkl

et al. 2006

Intl Journal of Cancer

271

201

View full text Add to dashboard Cite

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“…A number of clinical observations in human malignant melanoma underline the potential importance of the immune response in this disease (Old, 1981;Oettgen and Old, 1991;Ferrone, 1994;Mackensen et al, 1994). It is believed that the immune attack of infiltrating lymphocytes against melanoma cells may be responsible for the occurrence of spontaneous, partial or complete melanoma regression and for the concomitant destruction of melanocytes in benign lesions, leading to clinical phenomena, such as halo nevi, uveitis and vitiligo in melanoma patients.…”

mentioning

confidence: 99%

“…It is believed that the immune attack of infiltrating lymphocytes against melanoma cells may be responsible for the occurrence of spontaneous, partial or complete melanoma regression and for the concomitant destruction of melanocytes in benign lesions, leading to clinical phenomena, such as halo nevi, uveitis and vitiligo in melanoma patients. These observations, together with anecdotal and clinical reports of tumour regression after bacterial infections, application of bacterial vaccines or more specific immune interventions, suggest that melanoma is a good model for the evaluation of the various strategies of immune therapy (Old, 1981;Oettgen and Old, 1991;Ferrone, 1994;Mackensen et al, 1994). Recently, cytolytic T lymphocytes (CTL), which recognize and destroy tumour cells, have been isolated from blood-or from tumour-infiltrating lymphocytes of melanoma patients by numerous investigators (reviewed by Boon et al, 1994;Houghton, 1994).…”

mentioning

confidence: 99%

Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study

Möller

Sun²,

Dorbic³

et al. 1998

Br J Cancer

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Summary Recently, cytokine gene transfer into tumour cells has been shown to mediate tumour regression in animal models via immunomodulation. Consequently, a number of clinical protocols have been developed to treat cancer patients with cytokine gene-modified tumour cells. Here, we report the results of a clinical phase trial using for the first time autologous, interleukin 7 gene-modified tumour cells for vaccination of ten patients with disseminated malignant melanoma. Melanoma cells were expanded in vitro from surgically removed metastases, transduced by a ballistic gene transfer technique and were then injected after in vitro irradiation s.c. at weekly intervals. Clinically, there was no major toxicity except for mild fever, and no major clinical response towards vaccination was observed. Eight of ten patients completed the initial three s.c. vaccinations and were eligible for immunological evaluation. Post vaccination, peripheral mononuclear cells (PBMCs) were found to contain an increased number of tumour-reactive proliferative as well as cytolytic cells, as determined by a limiting dilution analysis. In three of six patients, the frequencies of anti-melanoma cytolytic precursor cells increased between 2.6-and 28-fold. Two of these patients showed a minor clinical response. Analysis of the autologous tumour cell vaccines regarding IL-7 secretion after gene transfer, HLA class and class 11 cell surface expression, secretion of immunosuppressive mediators (TGF-,1, IL-10) and various melanoma-associated tumour antigens revealed a very diverse expression profile. In conclusion, vaccination using gene-modified autologous melanoma cells induced immunological changes in a group of advanced, terminally ill patients. These changes can be interpreted as an increased anti-tumour immune response. However, immunological modulation was most pronounced in patients in good physical condition. Therefore, patients with minimal tumour load or minimal residual disease might preferentially benefit from tumour cell vaccination in further studies. In order to evaluate the effects of the cytokine gene-modified tumour cell vaccines more precisely, an antigenically better defined vaccine is needed.

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“…An immunosurveillance system for these molecules, known as the tumorassociated antigen (TAA), plays an important role in the elimination of cancer cells during the initial stage. [1][2][3] However, because tumor cells are inherently autologous cells and their immunogenicity is very weak as compared with pathogens (non-self) invading from the outside world, malignant tumor cells can evade immunosurveillance and then infringe upon various biological functions by uncontrollable proliferation and metastasis. In addition, several soluble factors secreted from tumor cells are known to induce failure in the host's immune function.…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressive efficacy through augmentation of tumor-infiltrating immune cells by intratumoral injection of chemokine-expressing adenoviral vector

et al. 2005

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Our goal in the present study was to evaluate antitumor effects and frequency of tumor-infiltrating immune cells upon intratumoral injection of RGD fiber-mutant adenoviral vector (AdRGD) encoding the chemokines CCL17, CCL19, CCL20, CCL21, CCL22, CCL27, XCL1, and CX3CL1. Among eight kinds of chemokine-expressing AdRGDs, AdRGD-CCL19 injection most efficiently induced infiltration of T cells into established B16BL6 tumor parenchyma, whereas most of these T cells were perforin-negative in immunohistochemical analysis. Additionally, the growth of AdRGD-CCL19-injected tumors decreased only slightly as well as that of other tumors treated with each chemokine-expressing AdRGD, which indicated that accumulation of naive T cells in tumor tissue does not effectively damage the tumor cells. Tumor-bearing mice, in which B16BL6-specific T cells were elicited by dendritic cellbased immunization, demonstrated that intratumoral injection of AdRGD-CCL17, -CCL22, or -CCL27 could considerably suppress tumor growth and attract activated T cells. On the other hand, AdRGD-CCL19-injection in the immunized mice showed slight increase of tumor-infiltrating T cells compared to treatment using control vector. Collectively, although AdRGD-mediated chemokine gene transduction into established tumors would be very useful for augmentation of tumor-infiltrating immune cells, a combinational treatment that can systemically induce tumor-specific effector T cells is necessary for satisfactory antitumor efficacy.

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Direct evidence to support the immunosurveillance concept in a human regressive melanoma.

Abstract: Clin. Invest. 1994.93:1397-1402

Cited by 155 publications

References 26 publications

Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses in vitro

Blockade of PD‐L1 (B7‐H1) augments human tumor‐specific T cell responses in vitro

Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study

Tumor suppressive efficacy through augmentation of tumor-infiltrating immune cells by intratumoral injection of chemokine-expressing adenoviral vector

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