Michel Buferne

Publications (11)42.42 Total impact

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  Available from: Nathalie Auphan-Anezin

  Dataset: auphan-anezin-pcmr12-2012

  Anne-Marie Schmitt-Verhulst, Saïdi M Soudja, Nathalie Auphan-Anezin, Michel Buferne, Amandine Mas, Maria Wehbe, Grégory Verdeil, Magali Grange
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  Available from: Nathalie Auphan-Anezin

  Article: Immunosuppression in inflammatory melanoma: can it be resisted by adoptively transferred T cells ?

  Nathalie Auphan-Anezin, Grégory Verdeil, Magali Grange, Saïdi M Soudja, Maria Wehbe, Michel Buferne, Amandine Mas, Anne-Marie Schmitt-Verhulst
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  ABSTRACT: Discovery of tumor antigens (TA) recognized by autologous T cells (TCs) in melanoma patients has led to clinical protocols using either vaccination or adoptive transfer of TA-specific TCs. However, efficacy of these treatments has been hampered by inhibitory effects exerted on tumor-infiltrating TCs by tumor-intrinsic mediators or by recruitment of immunosuppressive cells. A mouse model of autochthonous melanoma recapitulates some aspects of inflammatory melanoma development in patients. These include a systemic Th2/Th17-oriented chronic inflammation, recruitment of immunosuppressive myeloid cells and acquisition by tumor-infiltrating TCs of an "exhausted" phenotype characterized by expression of multiple inhibitory receptors including Programmed Death-1 (PD-1), also expressed on patients' melanoma-infiltrating TCs. Rather than using extra-cellular blocking reagents to inhibitory surface molecules on TCs, we sought to dampen negative signaling exerted on them. Adoptively transferred TCs presenting increased cytokine receptor signaling due to expression of an active Stat5 transcription factor were efficient at inducing melanoma regression in the pre-clinical melanoma model. These transferred TCs thrived and retained expression of effector molecules in the melanoma microenvironment, defining a protocol endowing TCs with the ability to resist melanoma-induced immunosuppression. © 2012 John Wiley & Sons A/S.
  Pigment Cell & Melanoma Research 12/2012; · 5.06 Impact Factor
• Article: Minimal tolerance to a tumor antigen encoded by a cancer-germline gene.

  Ivo J Huijbers, Saïdi M Soudja, Catherine Uyttenhove, Michel Buferne, Else-Marit Inderberg-Suso, Didier Colau, Luc Pilotte, Céline G Powis de Tenbossche, Patrick Chomez, Francis Brasseur, Anne-Marie Schmitt-Verhulst, Benoît J Van den Eynde
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  ABSTRACT: Central tolerance toward tissue-restricted Ags is considered to rely on ectopic expression in the thymus, which was also observed for tumor Ags encoded by cancer-germline genes. It is unknown whether endogenous expression shapes the T cell repertoire against the latter Ags and explains their weak immunogenicity. We addressed this question using mouse cancer-germline gene P1A, which encodes antigenic peptide P1A(35-43) presented by H-2L(d). We made P1A-knockout (P1A-KO) mice and asked whether their anti-P1A(35-43) immune responses were stronger than those of wild-type mice and whether P1A-KO mice responded to other P1A epitopes, against which wild-type mice were tolerized. We observed that both types of mice mounted similar P1A(35-43)-specific CD8 T cell responses, although the frequency of P1A(35-43)-specific CD8 T cells generated in response to P1A-expressing tumors was slightly higher in P1A-KO mice. This higher reactivity allowed naive P1A-KO mice to reject spontaneously P1A-expressing tumors, which progressed in wild-type mice. TCR-Vβ usage of P1A(35-43)-specific CD8 cells was slightly modified in P1A-KO mice. Peptide P1A(35-43) remained the only P1A epitope recognized by CD8 T cells in both types of mice, which also displayed similar thymic selection of a transgenic TCR recognizing P1A(35-43). These results indicate the existence of a minimal tolerance to an Ag encoded by a cancer-germline gene and suggest that its endogenous expression only slightly affects diversification of the T cell repertoire against this Ag.
  The Journal of Immunology 12/2011; 188(1):111-21. · 5.79 Impact Factor
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  Available from: Nathalie Auphan-Anezin

  Article: Activated STAT5 promotes long-lived cytotoxic CD8+ T cells that induce regression of autochthonous melanoma.

  Magali Grange, Michel Buferne, Grégory Verdeil, Lee Leserman, Anne-Marie Schmitt-Verhulst, Nathalie Auphan-Anezin
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  ABSTRACT: Immunotherapy based on adoptive transfer of tumor antigen-specific CD8(+) T cell (TC) is generally limited by poor in vivo expansion and tumor infiltration. In this study, we report that activated STAT5 transcription factors (STAT5CA) confer high efficiency on CD8(+) effector T cells (eTC) for host colonization after adoptive transfer. Engineered expression of STAT5CA in antigen-experienced TCs with poor replicative potential was also sufficient to convert them into long-lived antigen-responsive eTCs. In transplanted mastocytoma- or melanoma-bearing hosts, STAT5CA greatly enhanced the ability of eTCs to accumulate in tumors, become activated by tumor antigens, and to express the cytolytic factor granzyme B. Taken together, these properties contributed to an increase in tumor regression by STAT5CA-transduced, as compared with untransduced, TCs including when the latter control cells were combined with infusion of interleukin (IL)-2/anti-IL-2 complexes. In tumors arising in the autochthonous TiRP transgenic model of melanoma associated with systemic chronic inflammation, endogenous CD8(+) TCs were nonfunctional. In this setting, adoptive transfer of STAT5CA-transduced TCs produced superior antitumor effects compared with nontransduced TCs. Our findings imply that STAT5CA expression can render TCs resistant to the immunosuppressive environment of melanoma tumors, enhancing their ability to home to tumors and to maintain high granzyme B expression, as well as their capacity to stimulate granzyme B expression in endogenous TCs.
  Cancer Research 11/2011; 72(1):76-87. · 7.86 Impact Factor
• Article: Cooperative action of CD8 T lymphocytes and natural killer cells controls tumour growth under conditions of restricted T-cell receptor diversity.

  Anil Shanker, Michel Buferne, Anne-Marie Schmitt-Verhulst
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  ABSTRACT: In mice expressing a transgenic T-cell receptor (TCR; TCRP1A) of DBA/2 origin with reactivity towards a cancer-germline antigen P1A, the number of TCRP1A CD8+ T cells in lymphoid organs is lower in DBA/2 than in B10.D2 or B10.D2(x DBA/2)F1 mice. This reduction results from haemopoietic cell autonomous differences in the differentiation of the major histocompatibility complex class I-restricted TCRP1A thymocytes controlled by DBA/2 versus B10.D2-encoded genes. We report here that the lower number of TCRP1A CD8+ T cells in DBA/2 mice correlated with their poor resistance to P1A-expressing mastocytoma solid tumours. Functional potency of CD8+ cytolytic T lymphocytes (CTL) from the above strains was not compromised, but their number after expansion appeared to be influenced by their genetic background. Intriguingly, non-transgenic DBA/ 2 mice resisted P1A+ tumours more efficiently despite poor representation of P1A-specific CTL. This was partly the result of their more heterogeneous TCR repertoire, including reactivity to non-P1A tumour antigens because mice that had rejected a P1A+ tumour became resistant to a P1A) variant of the tumour. Such 'cross-resistance' did not develop in the TCRP1A transgenic mice. Nonetheless, reconstitution of RAGo/o mice with TCRP1A CD8+ T cells, with or without CD4+ T cells, or exclusive representation of TCRP1A CD8+ T cells in RAGo/o TCRP1A transgenic mice efficiently resisted the growth of P1A-expressing tumours. Natural killer cells present at a higher number in RAGo/o mice also contributed to tumour resistance, in part through an NKG2D-dependent mechanism. Hence, in the absence of a polyclonal T-cell repertoire, precursor frequencies of natural killer cells and tumour-specific CTL affect tumour resistance.
  Immunology 01/2010; 129(1):41-54. · 3.32 Impact Factor
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  Available from: Nathalie Auphan-Anezin

  Article: CD8 T cell help for innate antitumor immunity.

  Anil Shanker, Grégory Verdeil, Michel Buferne, Else-Marit Inderberg-Suso, Denis Puthier, Florence Joly, Catherine Nguyen, Lee Leserman, Nathalie Auphan-Anezin, Anne-Marie Schmitt-Verhulst
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  ABSTRACT: Innate immunity is considered to initiate adaptive antitumor responses. We demonstrate that monoclonal CD8 T lymphocytes reactive to tumor Ag P1A on P815 mastocytoma cells provide essential "help" to NK cells for rejection of P1A-deficient tumors. RAG-deficient mice have normal NK cells but do not reject either tumor. Reconstitution of these mice with P1A-specific T cells conferred resistance to both P1A-expressing and -deficient tumor cells provided they were present at the same site. Elimination of Ag-negative tumor variants required both activated T and NK cells. Gene expression profiling of NK cells infiltrating P1A-positive tumors in mice with specific CD8 T cells demonstrated an activated effector phenotype. However, CD8 T cell help to NK cells appeared ineffective for P1A-negative variants separated from the P1A-positive tumor. Local tumor Ag-specific T cell-NK cell collaboration results in the elimination of tumor cells whether they express or not the T cell tumor Ag epitope, thus containing the emergence of tumor escape variants before metastasis.
  The Journal of Immunology 12/2007; 179(10):6651-62. · 5.79 Impact Factor
• Article: Role of Ti/CD3, Thy‐1, and Ly‐6 in Cytolytic T‐Cell Activation Analyzed with Ti Loss Variantsa

  CLAIRE LANGLET, ANNICK GUIMEZANES, PIERRE KALDY, CLAUDE BOYER, MICHEL BUFERNE, MARTIN POENIE, ROGER TSIEN, OBERDAN LEO, JEFFREY BLUESTONE, LEE LESERMAN, ANNE-MARIE SCHMITT-VERHULST
  Annals of the New York Academy of Sciences 12/2006; 532(1):33 - 43. · 3.15 Impact Factor
• Article: Differential implication of protein kinase C isoforms in cytotoxic T lymphocyte degranulation and TCR-induced Fas ligand expression.

  Julián Pardo, Michel Buferne, María-José Martínez-Lorenzo, Javier Naval, Anne-Marie Schmitt-Verhulst, Claude Boyer, Alberto Anel
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  ABSTRACT: CD8(+) cytotoxic T lymphocyte (CTL) clones are able to exert both perforin- and Fas-dependent cytotoxicity. We show in the present work that phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 prevent TCR/CD3-induced functional Fas ligand (FasL) expression, but not perforin-dependent cytotoxicity. The specific inhibitor of classical protein kinase C (PKC) isoforms, Gö6976, completely inhibited perforin-dependent cytotoxicity and only affected slightly TCR/CD3-induced FasL expression, while the opposite was observed using rottlerin, an inhibitor with higher specificity for PKCtheta. To address further the dependence of FasL expression on PI3K, a luciferase reporter controlled by the FasL promoter was used. Reporter gene induction by anti-CD3 mAb was abolished in cells transfected with dominant-negative PI3K (PI3K-DN) and increased in cells transfected with constitutively active PI3K (PI3K*). Transfection with constitutively active mutants (A/E) of PKCepsilon, and especially of PKCtheta, improved anti-CD3 mAb-induced reporter expression and completely abolished inhibition by wortmannin, while transfection with dominant-negative (K/R) PKCtheta prevented the induction of the reporter. Finally, transfection with PKCalpha A/E, but not with PKCtheta A/E, cooperated with ionomycin to induce degranulation in the CTL line 1.3E6SN. Altogether, the results suggest that TCR/CD3-induced FasL gene transcription is controlled by PI3K and PKCtheta activation, while this signaling pathway is not implicated in CTL degranulation, which is rather dependent on the activation of classical PKC isoforms.
  International Immunology 01/2004; 15(12):1441-50. · 3.41 Impact Factor
• Article: T cell receptor‐induced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A

  Alberto Anel, Michel Buferne, Claude Boyer, Anne‐Marie Schmitt‐Verhulst, Pierre Golstein
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  ABSTRACT: Fas/APO-1 is a member of the tumor necrosis factor receptor family of proteins, that induces apoptosis when cross-linked with monoclonal antibody (mAb) or with its physiological ligand. Recently, both a perforin-based and a Fas-based mechanism have been proposed to account for T cell-mediated cytotoxicity. In the present study we used a murine CD8+ cytotoxic T lymphocyte (CTL) clone (KB5.C20) specific for H-2Kb and a T cell receptor (TcR)-negative variant of the same clone (2005−D4) to test (i) whether the same cell can exert both cytotoxic effector mechanisms and (ii) the role of TcR engagement in the induction of Fas-based cytotoxicity. We demonstrate that both the TcR+ and TcR− clones were able to express the Fas ligand after stimulation with phorbol 12-myristate 13-acetate (PMA)/ionomycin, and that TcR engagement of the KB5.C20 clone by means of antigen-bearing cells or of its anticlonotypic mAb (Désiré-1), which leads to Ca2+-dependent, presumably perforin-based, cytotoxicity, was also able to induce Fas-based cytotoxicity. In addition, using inhibitors we investigated the signal transduction pathway(s) involved in the induction of Fas-based cytotoxicity and expression of the Fas ligand mRNA in the CTL clones. The involvement of src-like protein tyrosine kinases (PTK) in Fas ligand induction through TcR engagement, was strongly suggested by inhibition with the src-like PTK inhibitor herbimycin A. Inhibition of Fas ligand induction by genistein, a more general TPK inhibitor, even upon stimulation by PMA plus ionomycin, suggested the possible involvement of PTK activities downstream of protein kinase C (PKC) in Fas ligand induction in CTL. Finally, the implication of the Ca2+/calmodulin-dependent protein phosphatase calcineurin in Fas ligand induction was demonstrated by the partial inhibition of Fas ligand induction with cyclosporin A. Thus, in CTL clones, Fas ligand expression is inducible by TcR engagement through a pathway similar to that involved in expression of some lymphokine genes.
  European Journal of Immunology 09/1994; 24(10):2469 - 2476. · 5.10 Impact Factor
• Article: Interactions between MHC-encoded products and cloned T-cells. I. Fine specificity of induction of proliferation and lysis

  Françoise Albert, Michel Buferne, Claude Boyer, Anne-Marie SchmittVerhulst
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  ABSTRACT: To study the interactions between T cells and class I MHC products, we developed in vitro a T-cell line reactive to H-2Kb stimulating cells and derived T-cell clones from it. Although the T-cell line could proliferate in the absence of exogeneous T-cell growth factors when stimulated with H-2Kb spleen cells, each of the derived T-cell clones required both H-2Kb stimulating cells and an external source of T-cell growth factor for its propagation. Each of the T-cell clones was also cytolysic for H-2Kb target cells. Such T-cell clones allowed the comparison of the antigenic requirements for proliferation and cytolysis. By using H-2K b mutant mice, we found that while the original anti-H-2Kb T-cell line reacted with each of the six mutants tested, the individual T-cell clones could be distinguished in terms of their reactivity pattern. Similar fine specificity patterns were found when H-2K b mutant cells were used as stimulating or target cells for any given T-cell clone. Each of the three monoclonal H-2Kb-specific antibodies reacting with different epitopes of the H-2Kb molecule totally inhibited H-2Kb-induced proliferation and lysis by the T-cell clones. Further blocking studies involved use of Fab antibody fragments and definition of their reactivity on cells from the H-2K b mutants. We concluded that: (1) blocking with a monoclonal antibody does not prove identity of alloantigens recognized by the T-cells and the antibody; (2) a monoclonal antibody could either block or not block H-2Kb-CTL interactions depending on structural variations of the H-2Kb molecule not affecting the CTL-H-2Kb functional interaction; (3) blocking one type of H-2Kb-T-cell interaction (induction of proliferation) always affects the other type (cytolysis).
  Immunogenetics 11/1982; 16(6):533-549. · 2.93 Impact Factor
• Article: TCR-Associated ζ-FcϵRlγ heterodimers on CD4−CD8− NK1.1+ t cells selected by specific class I MHC antigen

  S. John Curnow, Claude Boyer, Michel Buferne, Anne-Marie Schmitt-Verhulst
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  ABSTRACT: The origin of autoreactive CD4−CD8− T cells is largely unknown. In TCR transgenic (Tg) mice expressing the cognate class I MHCantigen, CD4−CD8−T cells differed depending on characteristics of Tg-TCR/antigen interaction. Tg-TCRJCD3lo CD4−CD8− T cells expressing the NK1.1 marker were observed only for a Tg-TCR whose stimulation by antigen was independent of CD8. Unlike normal T cells, which have essentially TCR-associated ζ homodimers, these cells had a high proportion of TCR-associated ζ-FcϵRlγ heterodimers. They were also characterized by an unusually high content of FcϵRlγ mRNA and low content of mRNA encoding CD3ϵ, CD3γ, CD3δ, and ζ. Based on their phenotype and selection requirements, it is proposed that CD4−CD8− thymic precursor cells can be driven along the CD4−CD8−NK1.1+ pathway following coreceptor-independent TCR signaling at an intrathymic stage when FcϵRlγ and CD3 components are coexpressed.
  Immunity.