Showing papers by "Wolf H. Fridman published in 2012"

The immune contexture in human tumours: impact on clinical outcome

Abstract: Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.

Overall Neutralization of Complement Factor H by Autoantibodies in the Acute Phase of the Autoimmune Form of Atypical Hemolytic Uremic Syndrome

Abstract: Complement is a major innate immune surveillance system. One of its most important regulators is the plasma protein factor H (FH). FH inactivation by mutations or by autoantibodies is associated with a thrombotic microangiopathy disease, atypical hemolytic uremic syndrome. In this study, we report the characterization of blood samples from 19 anti-FH Ab-positive atypical hemolytic uremic syndrome patients collected at the acute phase of the disease. Analyses of the functional consequences and epitope mapping, using both fluid phase and solid phase approaches, were performed. The anti-FH Abs perturbed FH-mediated cell protection (100%), inhibited FH interaction with C3 (46%), and caused C3 consumption (47%). The Abs were directed against multiple FH epitopes located at the N and C termini. In all tested patients, high titers of FH-containing circulating immune complexes were detected. The circulating immune complex titers correlated with the disease stage better than did the Ab titers. Our results show that anti-FH autoantibodies induce neutralization of FH at acute phase of the disease, leading to an overall impairment of several functions of FH, extending the role of autoantibodies beyond the impairment of the direct cell surface protection.

Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer.

Abstract: CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb…) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors,etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators.

Tumor microenvironment in NSCLC suppresses NK cells function

Abstract: NK cells, which contribute to tumor immunosurveillance, are present in the microenvironment of Non-Small-Cell Lung Carcinoma. However, they display strongly altered phenotype with decreased expression of NKp30, NKp80, DNAM-1, CD16 and ILT2, and impaired cytotoxic functions. The possible mechanisms leading to these defects are discussed.

The immune microenvironment as a guide for cancer therapies

Abstract: After a long period of disputed history made of great hopes and subsequent disillusions, the field of oncoimmunology has now reached an unprecedented level of recognition and respectability, both in the scientific world and in the medical universe. This results from the merge of two streams of thought. The first stream resulted from the availability of recombinant strains of mice lacking some or all components of the immune system, sometimes crossed with mice transgenic for oncogene expression, yielding the demonstration that the lack of immune components favors spontaneous tumor development. These experiments have generated the 3E’s theory, which describes the three phases of tumor development, paraphrased as elimination, equilibrium, and escape. At the initiation of oncogenesis, most nascent tumor cells would be eliminated by the immune system. Only after genetic and phenotypic editing, prospective cancer cells may form a tumor that establishes an equilibrium with the immune surveillance system. Finally, tumor cells will undergo further (epi)mutations and escape immune control. This theory implies that advanced tumors become resistant to immune attack and advanced cancer patients should therefore not respond to immunotherapy. The second stream, however, resulted from the success of immunotherapeutic approaches in advanced cancers including metastatic disease. Thus, monoclonal antibodies recognizing tumor cell associated antigens were proven efficient in lymphoma (CD20), colorectal (EGF-R) and breast (HER2-neu) cancer. Their beneficial effect is mediated, at least partly, through immune stimulation, for instance by activating NK cells via the FcγRIII (CD16) receptors and by inducing a memory T-cell response against the targeted antigen. Monoclonal antibodies raised against lymphocyte “checkpoint” receptors (CTLA-4, PD1, CD137) or their ligands (PDL-1) were reported to increase patient survival in metastatic melanoma, colorectal, pancreatic cancers or lymphoma. That the anti-tumor effect was indeed the consequence of unlocking the immune system is supported by the concomitant induction of autoimmune reactions in patients treated with anti-checkpoint antibodies and by the fact that responding metastatic sites become highly infiltrated by CD8+ T cells. Therapeutic vaccination of patients with metastatic, hormone refractory prostate cancer resulted in significant increase in overall survival accompanied by a specific immune response to the immunizing prostatic antigens. Finally, cellular therapies with precursor or differentiated T cells, sometimes engineered to express a TCR that recognizes a tumor-associated antigen, can induce spectacular tumor regressions and prolong overall survival. Beyond these “classical” immunotherapies, a recent revolutionary concept suggests that chemotherapies are effective to induce prolonged overall survival only if they stimulate an anticancer immune response, for instance by inducing immunogenic tumor cell death that de facto converts the cancer into a therapeutic vaccine. Established in murine models, this concept is supported in man by the fact that polymorphisms of molecules involved in immunogenic chemotherapies are associated with patient survival. Also, some anti-angiogenic therapies may modulate the patient immune system by downregulating suppressor cells. Therefore, a large body of murine models and clinical trials is largely supportive of the fact that the immune system is involved in tumor control and that its manipulation may result in increased survival, even in patients with advanced cancer. The effectiveness of immunotherapies requires the stimulation of anticancer immune responses. It has been established for a long time that, except at the terminal stage or in heavily pretreated patients, cancer patients maintain a functional immune system capable of protecting them from infections. The last decade has witnessed the analyses of large cohorts of cancer patients, allowing to demonstrate that the tumor’s immune microenvironment influences clinical outcome. Thus, a high density of memory T cells with a Th1 cytokine pattern and cytotoxic phenotype is a major positive prognostic factor correlating with increased survival of patients with colorectal, breast, urothelial, lung, gastric, pancreatic, ovarian, bladder, hepatocellular, cervical carcinomas, as well as with melanoma. This observation has led to the proposal of a new prognostic classification based on the immune pattern of the tumor microenvironment. This immune pattern is predictive of survival at all stage of cancer progression. For instance, in colorectal cancer, 95% of the patients with local disease (no lymph node or distant metastases) exhibiting high infiltration of CD8+ and memory cells (CD45RO+) of the tumor were alive after 5 y, as compared with 27% with low densities of these cells. Even at the disseminated stage, patients with a high memory T cell infiltrate in their resected hepatic metastases respond better to chemotherapy and exhibit a better overall survival than patients with a low T cell infiltrate in their metastatic sites. Altogether, these data support the concept that an efficient immune reaction may be shaped in the tumor microenvironment, then circulate as memory cells in the organism and finally delay recurrence post therapy and cancer-associated death. The question therefore arises of which patients would benefit from immunotherapeutic approaches. This problem is far from being trivial because, once resolved, it will result in the selection of patients for immunotherapy, particularly in early stage cancers. Treating an unselected cohort of early-stage patients for which the expected survival time is > 95% at 5 y is unlikely to yield statistically meaningful results unless very large trials are envisaged. In contrast, patients with a depressed immune system and advanced, aggressive cancer are unlikely to respond to any kind of therapy including immunotherapy. A definite proposal on which patients should experience immuntherapy is therefore difficult to establish, and murine models that reflect different interactions between cancer and the immune system should be designed and studied. Before robust pre-clinical data guide future immunotherapies, however, several rules could be proposed for the further evaluation and optimization of anticancer immunotherapies. The first rule would be to obligatorily characterize the immune pattern of the tumor in all patients that are renrolled in the trial, thus allowing to establish retrospective classifications. The second rule would be to launch prospective trials in which the immune pattern is established for each patient. The third rule would be to preferentially treat early-stage patients with a low density of intratumoral memory T and CD8 cells with the aim of obtaining a clinical response within a short timeframe. Conversely, at the metastatic stage, only patients with signs of an efficient anticancer immune response should be included in innovative clinical trials. We can anticipate that appropriate mouse models as well as intelligently designed clinical trial will fine tune optimal antineoplastic therapies as they demonstrate an ever more important role of the anticancer immune response.

Influence of Tumor Location on the Composition of Immune Infiltrate and Its Impact on Patient Survival. Lessons from DCBCL and Animal Models.

Abstract: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous diseases growing either in nodal or extranodal locations including the central nervous system. One key issue is to decipher the prognosis value of immune cells infiltrating these tumors as DLBCLs developing in sanctuaries are more aggressive than nodal DLCBLs. Here, we summarize available data from the literature regarding the prognostic values of the different immune cell types found in these two types of human primary tumors (ie nodal vs brain). In nodal DLBCLs, memory T-cells and dendritic cells (DCs) densities are of good prognostic value whereas the influence of regulatory T-cells (Tregs) is less clear, in accordance with other types of cancers. Datas for primary central nervous system lymphomas (PCNSLs) are very sparse for these cell types. By contrast, CD8+ cytotoxic T-cells seem to be of poor prognosis in either location. Their presence is linked to a loss of MHC expression providing a possible immune escape mechanism for these tumors. Clearly, tumor associated macrophages are not associated to a significant prognostic value even in the brain where they highly infiltrate the tumor. Animal models indicate some specific features of lymphoma developing in sanctuaries by comparison to splenic location, with a higher infiltration of Tregs and less DCs, most likely reflecting the immunosuppressive context of these organs. All these informations illustrate the high impact of the immune system on patient outcome, encourage the pursuit of the immune environment’s analysis and of immunotherapeutic approaches.

In vitro method for prognostication of progression and outcome of cancer in patient and means for implementing said method

Abstract: PROBLEM TO BE SOLVED: To provide a new method for prognostication of the outcome of a cancer in a patient.SOLUTION: For a positive outcome of a cancer, data for good prognosis of survival time of a patient is provided by quantification of a high density of CD3+ cells, CD8+ cells, CD45RO+ cells or Granzyme-B+ cells at the site of a tumor, either in the central part of the tumor or in the invasive margin thereof; and by comparing prescribed reference values with quantitative values obtained for the cell density of at least one cell type in a CT tumor tissue sample and an IM tumor tissue sample.