In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis

Saudemont, Aurore; Quesnel, Bruno

doi:10.1182/blood-2004-01-0064

Cited by 158 publications

(191 citation statements)

References 46 publications

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“…30 We found in our system that PD-1/PD-L1-blockade improved IFN-g production independent of the presence or absence of CD80 costimulation. In contrast to previous murine data using PD-L1 overexpressing leukemia cells as stimulators, 77 we found no synergistic effects of blockade of PD-L1 and CD80. Taking together, we thus conclude (in line with our and others previous data from mouse models) that PD-L1 plays a more critical role at the effector phase of T cell responses.…”

Section: Discussioncontrasting

confidence: 56%

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

272

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: Discussioncontrasting

confidence: 56%

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

272

201

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“…7,8 Briefly, DA1 IL3-dependent cells were electroporated with a pCDNA3 expression vector (Invitrogen, San Diego, CA, USA) carrying a p210 BCR/ABL cDNA, and transduced cells were selected by culture in IL3-free medium. Imatinib (Novartis Pharmaceuticals, East Hanover, NJ, USA) was stored at À20 1C as a 10 mM stock solution in distilled water.…”

Section: Cell Line and Kinase Inhibitorsmentioning

confidence: 99%

BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

et al. 2008

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Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL þ leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K þ T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.

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“…82 such as B7H1 (also known as CD274 antigen and programmed cell death 1 ligand 1) or B7.1 (B-lymphocyte activation antigen B7) that induce apoptosis of cytotoxic CD8 + T lymphocytes. [61][62][63][64] Taken together, these results suggest that in some situations the immune system might still be operating to suppress residual tumor cell expansion. Therefore, an equilibrium between the immune response and tumor response and tumor cells leads longterm dormancy.…”

Section: C) Alterations In the P38 Kinase/erk-1/2 Ratio And Interactimentioning

confidence: 73%

Target-based agents in neo-adjuvant treatment of liver metastases from colo-rectal cancer: Secret weapons in anticancer war?

Marra

Giudice

Arra

et al. 2009

Cancer Biology & Therapy

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Target based agents in neo-adjuvant treatment of liver metastasesThe therapeutic options for liver metastases of colorectal cancer mainly include surgical resection and palliative chemotherapy. More recently, the increased availability of new and more active cytotoxic drugs has increased the appeal of a combined treatment strategy, in which chemotherapy is administered before surgery. However, the efficacy of neoadjuvant chemotherapy of CRC liver metastases is limited by: (1) the persistence of micro metastatic foci that cannot be seen by conventional imaging techniques, placed either in other sites throughout the liver and/or in the site of the previous macroscopic metastasis that has undergone to clinical complete response; (2) the occurrence of escape mechanisms. The molecular basis regulating these processes are described and the first clinical attempts to overcome these mechanisms through the use of target-based agents are also reported. Finally, biological rationales to optimize the activity of these agents in neoadjuvant setting are discussed.

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In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis

Cited by 158 publications

References 46 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

BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

Target-based agents in neo-adjuvant treatment of liver metastases from colo-rectal cancer: Secret weapons in anticancer war?

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