PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells

Iwai, Yoshiko; Terawaki, Seigo; Honjo, Tasuku

doi:10.1093/intimm/dxh194

Cited by 453 publications

(319 citation statements)

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“…39 Data from experiments using transfected human tumor cell lines and from animal models indicate a negative regulatory role of PD-L1 on tumor cells for tumor-specific T cells, resulting in impaired immune control of tumor growth and spread. [20][21][22]41 However, to our knowledge, the functional relevance of endogenous (and thus lower) PD-L1 expression on tumor cells towards human tumor-specific T cells has not been examined so far. Our study supports the hypothesis of PD-L1 as a mediator of tumor escape from tumor-specific T cells.…”

Section: Discussionmentioning

confidence: 99%

“…40 Animal models revealed an improved tumor rejection from PD-1 deficient tumor-specific T cells 20,22 and decreased spread of poorly immunogenic melanoma and colon carcinoma cells in PD-1 deficient animals. 41 Furthermore, PD-L1 was shown to be expressed at high levels on human glioma cells, and its blockade was shown to increase T cell function upon polyclonal stimulation. 42 In addition, PD-L1 was found to be expressed at increased levels on murine monocyte-derived dendritic cells (DCs) collected from cancer tissues.…”

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

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Kuball

Voelkl

et al. 2006

Intl Journal of Cancer

274

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: Discussionmentioning

confidence: 99%

mentioning

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

274

201

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“…[35][36][37] Conversely, there remains a problem regarding PD-1/PD-L1 blockade because of the possible expansion of poorly immunogenic cells. 38 Further studies may be required to clarify the therapeutic effect of PD-1/PD-L1 blockade in malignant melanoma models and clinical trials.…”

Section: Pd-l1 Expression In Malignant Melanomamentioning

confidence: 99%

Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma

Hino

Kabashima

Kato

et al. 2010

Cancer

610

419

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BACKGROUND: Melanoma tends to be refractory to various immunotherapies because of tumor-induced immunosuppression. To investigate the mechanism underlining the immunosuppression of melanoma patients, the authors focused on programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) interaction between tumor cells and T cells. METHODS: Melanoma specimens were collected from 59 primary tumors, 16 lymph nodes, and 4 lesions of in-transit metastasis. Specimens stained with anti-PD-L1 monoclonal antibodies were digitalized to jpg files. To evaluate the intensity of PD-L1 expression, histograms were used, and the red density (RD) was measured. PD-1 expression on T cells was analyzed in blood samples from 10 patients who had stage IV melanoma and in 4 samples of in-transit metastases. RESULTS: Twenty-five patients comprised the ''low'' PD-L1 expression group (RD value, <90), and 34 patients comprised the ''high'' group (RD value, !90). Breslow tumor thickness in the high-expression group was significantly higher than in the low-expression group. Univariate and multivariate analyses revealed that the overall survival rate of the high-expression group was significantly lower than that of the low-expression group. In all patients with stage IV disease who were examined, both CD8-positive and CD4-positive T cells had significantly higher PD-1 expression levels in the peripheral blood. Tumor-infiltrating T cells expressed high levels of PD-1, and its expression was elevated further during the clinical course. CONCLUSIONS: The current results indicated that there is a correlation between the degree of PD-L1 expression and the vertical growth of primary tumors in melanoma. Multivariate analysis demonstrated that PD-L1 expression is an independent prognostic factor for melanoma. Cancer 2010;116:1757-66.

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“…Tumor-secreted IL-10 and VEGF also induce expression of B7-H1 on myeloid dendritic cells, a ligand for PD-1 receptor expressed on suppressor T cells [238]. A study published this year demonstrates that the metastatic ability of melanoma and colon cancer cells expressing B7-H1 is abolished in PD-1-deficient mice and that tumors also grow more slowly [239]. These and other experiments indirectly show that tumor cell escape from immunosurveillance -in this case mediated by modulation of myeloid DC and suppressive T cell function -is essential for tumor growth and metastasis.…”

Section: Nks and Dcsmentioning

confidence: 99%

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

Kopfstein

Christofori

2006

Cell. Mol. Life Sci.

210

160

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Abstract. The fatality of cancer predominantly results from the dissemination of primary tumor cells to distant sites and the subsequent formation of metastases. During tumor progression, some of the primary tumor cells as well as the tumor microenvironment undergo characteristic molecular changes, which are essential for the metastatic dissemination of tumor cells. In this review, we will discuss recent insights into pro-metastatic events occurring in tumor cells themselves and in the tumor stroma. Tumor cell-intrinsic alterations include the loss of cell polarity and alterations in cell-cell and cell-matrix Cell. Mol. Life Sci. 63 (2006) 449-468 1420-682X/06/040449-20 DOI 10.1007/s00018-005-5296-8 © Birkhäuser Verlag, Basel, 2006 adhesion as well as deregulated receptor kinase signaling, which together support detachment, migration and invasion of tumor cells. On the other hand, the tumor stroma, including endothelial cells, fibroblasts and cells of the immune system, is engaged in an active molecular crosstalk within the tumor microenvironment. Subsequent activation of blood vessel and lymph vessel angiogenesis together with inflammatory and immune-suppressive responses further promotes cancer cell migration and invasion, as well as initiation of the metastatic process.

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PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells

Cited by 453 publications

References 48 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

Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

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