Showing papers by "Wolf H. Fridman published in 2014"
TL;DR: B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell-mediated immunity.
Abstract: Rationale:Itisnowwellestablishedthatimmuneresponsescantake place outside of primary and secondary lymphoid organs. We previously described the presence of tertiary lymphoid structures (TLS) in patients with non–small cell lung cancer (NSCLC) characterized by clusters of mature dendritic cells (DCs) and T cells surrounded by B-cell follicles. We demonstrated that the density of these mature DCs was associated with favorable clinical outcome. Objectives: To study the role of follicular B cells in TLS and the potentiallinkwithalocalhumoralimmuneresponseinpatientswith NSCLC. Methods: The cellular composition of TLS was investigated by immunohistochemistry. Characterization of B-cell subsets was performedby flowcytometry.Aretrospectivestudywasconductedin two independent cohorts of patients. Antibody specificity was analyzed by ELISA. Measurements and Main Results: Consistent with TLS organization, all stages of B-cell differentiation were detectable in most tumors. Germinal center somatic hypermutation and class switch recombination machineries were activated, associated with the generation of plasma cells. Approximately half of the patients showed antibody reactivity against up to 7 out of the 33 tumor antigens tested. A high density of follicular B cells correlated with long-termsurvival,bothinpatientswithearly-stageNSCLCandwith advanced-stage NSCLC treated with chemotherapy. The combination of follicular B cell and mature DC densities allowed the identification of patients with the best clinical outcome. Conclusions: B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell–mediated immunity.
514 citations
TL;DR: These results show how tumors infiltrated by TLS-associated mature DC generate a specific immune contexture characterized by a strong Th1 and cytotoxic orientation that confers the lowest risk of death.
Abstract: Tumor-infiltrating T cells, particularly CD45RO(+)CD8(+) memory T cells, confer a positive prognostic value in human cancers. However, the mechanisms that promote a protective T-cell response in the tumor microenvironment remain unclear. In chronic inflammatory settings such as the tumor microenvironment, lymphoid neogenesis can occur to create local lymph node-like structures known as tertiary lymphoid structures (TLS). These structures can exacerbate a local immune response, such that TLS formation in tumors may help promote an efficacious immune contexture. However, the role of TLS in tumors has yet to be investigated carefully. In lung tumors, mature dendritic cells (DC) present in tumor-associated TLS can provide a specific marker of these structures. In this study, we evaluated the influence of TLS on the characteristics of the immune infiltrate in cohorts of prospective and retrospective human primary lung tumors (n = 458). We found that a high density of mature DC correlated closely to a strong infiltration of T cells that are predominantly of the effector-memory phenotype. Moreover, mature DC density correlated with expression of genes related to T-cell activation, T-helper 1 (Th1) phenotype, and cytotoxic orientation. Lastly, a high density of TLS-associated DC correlated with long-term survival, which also allowed a distinction of patients with high CD8(+) T-cell infiltration but a high risk of death. Taken together, our results show how tumors infiltrated by TLS-associated mature DC generate a specific immune contexture characterized by a strong Th1 and cytotoxic orientation that confers the lowest risk of death. Furthermore, our findings highlight the pivotal function of TLS in shaping the immune character of the tumor microenvironment, in promoting a protective immune response mediated by T cells against cancer.
416 citations
TL;DR: Evidence for the roles of TLS in chronic infection, autoimmunity, and cancer, and the question of whether TLS present beneficial or deleterious effects in these contexts are discussed.
378 citations
French Institute of Health and Medical Research1, Katholieke Universiteit Leuven2, Ben-Gurion University of the Negev3, German Cancer Research Center4, Istituto Superiore di Sanità5, University of Turin6, Georgia Regents University7, University of Oxford8, Cardiff University9, Oregon Health & Science University10, Yale University11, Cold Spring Harbor Laboratory12, University of Pennsylvania13, University of Burgundy14, National Institutes of Health15, Georgetown University16, University of Miami17, Icahn School of Medicine at Mount Sinai18, GlaxoSmithKline19, University of Paris20, Centre national de la recherche scientifique21, Heidelberg University22, University of Pittsburgh23, Karolinska Institutet24, Hamad Medical Corporation25, University of Sheffield26, Centre Hospitalier Universitaire de Toulouse27, University of Lausanne28, University of Milan29, University of Navarra30, Leiden University31, University of Texas Health Science Center at Houston32, Istituto Giannina Gaslini33, Roswell Park Cancer Institute34, University of California, San Francisco35, Northwestern University36, Johns Hopkins University37, Main Line Health38, Thomas Jefferson University39, University of Buenos Aires40, Memorial Sloan Kettering Cancer Center41, University of Chicago42, Martin Luther University of Halle-Wittenberg43, Mie University44, University of Lisbon45, University of Queensland46, QIMR Berghofer Medical Research Institute47, Ludwig Institute for Cancer Research48, University of Connecticut49, University of Nebraska Medical Center50, Université catholique de Louvain51, Mayo Clinic52, Technische Universität München53, University of South Florida54, Cornell University55, University of Michigan56
TL;DR: A critical, integrated classification of anticancer immunotherapies is proposed and the clinical relevance of these approaches is discussed.
Abstract: During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
375 citations
TL;DR: The results show that chromosome instability contributes to the regulation of cytokines and downstream tumor immune response, and underline the major role of IL15 in human tumors.
Abstract: The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival. Decreased IL15 expression affected the local proliferation of B and T lymphocytes. Patients with proliferating B and T cells at the invasive margin and within the tumor center had significantly prolonged disease-free survival. These results delineate chromosomal instability as a mechanism of modulating local cytokine expression in human tumors and underline the major role of IL15. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumor, and the importance of local active lymphocyte proliferation for patient survival.
186 citations
TL;DR: This model highlights a novel tumour cell-dependent immune contexture that predicts patient's clinical outcome and has implications in the use of immunotherapies.
113 citations
TL;DR: It is demonstrated that the injection of TLR7 agonist in NOD/SCID mice, in C57BL/6 wild-type, andTLR7-deficient mice grafted with lung adenocarcinoma tumor cells leads to increased tumor progression and chemotherapeutic resistance.
Abstract: Toll-like receptors (TLR) recognize pathogen molecules and danger-associated signals that stimulate inflammatory processes. TLRs have been studied mainly in antigen-presenting cells, where they exert important immune regulatory functions, but they are also expressed by epithelial tumor cells, where they have been implicated in tumor progression. In this study, we demonstrate that the injection of TLR7 agonist in NOD/SCID mice, in C57BL/6 wild-type, and TLR7-deficient mice grafted with lung adenocarcinoma tumor cells leads to increased tumor progression and chemotherapeutic resistance. In patients with non-small cell lung cancer, expression analyses revealed that high TLR7 expression was strongly associated with resistance to neoadjuvant chemotherapy and poor clinical outcomes. Our findings delineate a crucial role for TLR7 in lung cancer physiopathology. Cancer Res; 74(18); 5008-18. ©2014 AACR.
87 citations
TL;DR: The immune contexture of human primary and metastatic tumors is described, how it impacts on patient outcomes and how it could be used as a predictive biomarker and guide immunotherapies are described.
Abstract: Cancer is a major public health issue and figures among the leading causes of death in the world. Cancer development is a long process, involving the mutation, amplification or deletion of genes and chromosomal rearrangements. The transformed cells change morphologically, enlarge, become invasive and finally detach from the primary tumor to metastasize in other organs through the blood and/or lymph. During this process, the tumor cells interact with their microenvironment, which is complex and composed of stromal and immune cells that penetrate the tumor site via blood vessels and lymphoid capillaries. All subsets of immune cells can be found in tumors, but their respective density, functionality and organization vary from one type of tumor to another. Whereas inflammatory cells play a protumoral role, there is a large body of evidence of effector memory T cells controlling tumor invasion and metastasis. Thus, high densities of memory Th1/CD8 cytotoxic T cells in the primary tumors correlate with good prognosis in most tumor types. Tertiary lymphoid structures, which contain mature dendritic cells (DC) in a T cell zone, proliferating B cells and follicular DC, are found in the tumor stroma and they correlate with intratumoral Th1/CD8 T cell and B cell infiltration. Eventually, tumors undergo genetic and epigenetic modifications that allow them to escape being controlled by the immune system. This comprehensive review describes the immune contexture of human primary and metastatic tumors, how it impacts on patient outcomes and how it could be used as a predictive biomarker and guide immunotherapies.
67 citations
TL;DR: This intricate network of interactions results in control or escape of tumors, and its understanding will help define goals to monitor efficiency of immunotherapies.
Abstract: A high density of intratumoral effector memory CD8+/Th1 T cells is associated with favorable prognosis in most cancers and may be induced or increased by immunotherapy. Efficient adaptive immune reactions are shaped in tumor adjacent tertiary lymphoid structures, which exhibit all characteristics of immunity generating lymphoid formations in reactive lymph nodes. Malignant tumor cells impact favorably or deleteriously their immune microenvironment if they bear genetic mutations that result in neo-antigens or by producing chemokines and cytokines that recruit lymphocytes and myeloid cells or increase inflammation and neo-angiogenesis. This intricate network of interactions results in control or escape of tumors, and its understanding will help define goals to monitor efficiency of immunotherapies.
29 citations
TL;DR: This recent study implicates tertiary lymphoid structures in the shaping of an efficient and beneficial immune response in lung cancer patients.
Abstract: T-cell infiltrates are robust prognostic biomarkers in the majority of human cancers. However, the mechanisms that shape a protective T-cell response remain unclear. Our recent study implicates tertiary lymphoid structures in the shaping of an efficient and beneficial immune response in lung cancer patients.
26 citations
TL;DR: In addition, the presence of a forte reaction immunitaire de type Th1/cytotoxique memoire peut prevenir la transition de tumeurs benignes vers des cancers and controler la croissance et linvasivite des cellules tumorales meme au stade metastatique.
Abstract: Les tumeurs se developpent au sein d’un microenvironnement cellulaire et tissulaire complexe. Celui-ci n’est pas inerte ; ses composants influencent l’evolution de la maladie, certains l’accelerent, d’autres la freinent. Des les premieres etapes de la transition d’un tissu normal a un tissu dysplasique, puis tumoral benin, puis tumoral malin et enfin jusqu’aux metastases, les interactions potentielles entre les cellules transformees et leur microenvironnement orientent l’evolution de ces processus. Un tissu siege d’une inflammation chronique favorise l’apparition de tumeurs, lesquelles, par les facteurs de neoangiogenese, d’immunosuppression et d’inflammation qu’elles produisent, renforcent les proprietes nourricieres et energetiques de leur microenvironnement. A l’oppose, la presence d’une forte reaction immunitaire de type Th1/cytotoxique memoire peut prevenir la transition de tumeurs benignes vers des cancers et controler la croissance et l’invasivite des cellules tumorales meme au stade metastatique. La connaissance de ces multiples phenomenes, decrits dans les differents articles de ce numero thematique de medecine/sciences, a un impact clinique majeur, puisque de nouveaux tests pronostiques et des approches therapeutiques efficaces ciblant le microenvironnement tumoral sont aujourd’hui en plein developpement.