Publications by authors named "Wolf-Herman Fridman"

Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics and high-dimensional flow cytometry to profile the monocyte-to-TAM transition.

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Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC).

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Article Synopsis
  • A randomized phase 2 trial was conducted to evaluate the effectiveness of neoadjuvant immune checkpoint blockade (ICB) therapies (nivolumab and nivolumab/ipilimumab) in patients with resectable retroperitoneal DDLPS and extremity/truncal UPS.
  • The primary endpoint of pathologic response showed a median hyalinization of 8.8% in DDLPS and 89% in UPS, with secondary endpoints focusing on immune changes and survival rates over time.
  • Results indicated that lower pre-treatment regulatory T cell densities correlated with better pathological outcomes, and that neoadjuvant ICB led to significant immune changes and benefits, particularly in patients with UPS when combined with radiation therapy
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The intricate relationship between anti-tumor immunity and autoimmunity is a complex yet crucial aspect of cancer biology. Tumor microenvironment often exhibits autoimmune features, a phenomenon that involves natural autoimmunity and the induction of humoral responses against self-antigens during tumorigenesis. This induction is facilitated by the orchestration of anti-tumor immunity, particularly within organized structures like tertiary lymphoid structures (TLS).

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Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown.

Experimental Design: We investigated the methylome of six ccRCC cohorts as well as one cell line dataset.

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Article Synopsis
  • Researchers conducted a phase 2 trial to evaluate the effectiveness and safety of nivolumab, nivolumab-ipilimumab, and VEGFR-TKIs in patients with metastatic clear-cell renal cell carcinoma based on their tumor's molecular characteristics.
  • The study included eligible patients from 15 healthcare centers in France, assigning them to different treatment groups through a randomized approach.
  • The primary goal was to assess how well these treatments worked, measured by the objective response rate, with safety also being monitored among patients receiving at least one dose of the medication.
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The omics era made possible the quest for efficient markers for cancer progression and revealed that macrophage populations are much more complex than just the M1/M2 dichotomy. Complement C1q pops up as a marker of a tolerogenic and immunosuppressive macrophage populations in both healthy and tumor tissues, but the specific role of C1q+ tumor-associated macrophages (TAM) is poorly understood. C1q is co-expressed in healthy and tumor macrophages with human leukocyte antigen DR (HLA-DR), Apolipoprotein E (APOE), and mannose receptor C-type 1 (MRC1) (CD206), suggesting a resident origin of this population.

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The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation.

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Whereas T cells have been considered the major immune cells of the tumor microenvironment able to induce tumor regression and control cancer clinical outcome, a burst of recent publications pointed to the fact that B cells may also play a prominent role. Activated in germinal centers of tertiary lymphoid structures, B cells can directly present tumor-associated antigens to T cells or produce antibodies that increase antigen presentation to T cells or kill tumor cells, resulting in a beneficial clinical impact. Immune complexes can also increase inflammation, angiogenesis, and immunosuppression via macrophage and complement activation, resulting in deleterious impact.

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Tumors progression is under the control of a heterogeneous microenvironment composed of immune cells, fibroblasts, blood and lymphatic vessels, in which T cells have been demonstrated to be major actors, through their cytotoxic and cytokine producing effector functions and their long term memory that protects against metastasis. In this scenario, lessons from mouse models taught that B cells exert a protumoral role, via macrophage-dependent activation of inflammation. However, it became progressively evident from studies in patients with human cancers that the anti-tumor responses can be generated and controlled in tertiary lymphoid structures (TLS) that concentrate most of the intratumoral B cells and where B cells can differentiate into plasma cells and memory cells.

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Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age.

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Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity, although these have been less well-studied in ICB treatment.

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The tumour microenvironment (TME) highly influences the growth and spread of tumours, thus impacting the patient's clinical outcome. In this context, the complement system plays a major and complex role. It may either act to kill antibody-coated tumour cells, support local chronic inflammation or hamper antitumour T cell responses favouring tumour progression.

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Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours. Key common characteristics between secondary lymphoid organogenesis and TLS neogenesis have been identified. TLSs exist under different maturation states in tumours, culminating in germinal centre formation.

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In colorectal cancer (CRC), T-cell checkpoint blockade is only effective in patients diagnosed with mismatch repair-deficient (MMR-d) cancers. However, defects in Human Leukocyte Antigen (HLA) class I expression were reported to occur in most MMR-d CRCs, which would preclude antigen presentation in these tumours, considered essential for the clinical activity of this immunotherapeutic modality. We revisited this paradox by characterising HLA class I expression in two independent cohorts of CRC.

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A high density of tumor-infiltrating CD8 T cells and CD20 B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP DCs is robustly associated with an immune contexture characterized by T1 polarization and cytotoxic activity.

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The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome.

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Background & Aims: Tertiary lymphoid structures (TLSs) provide a local and critical microenvironment for generating anti-tumor cellular and humoral immune responses. TLSs are associated with improved clinical outcomes in most solid tumors investigated to date. However, their role in hepatocellular carcinoma (HCC) is debated, as they have recently been shown to promote the growth of malignant hepatocyte progenitors in the non-tumoral liver.

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Fc-receptors for immunoglobulin G (FcγRs) mediate a variety of effector and regulatory mechanisms in the immune system. N-glycosylation of FcγRs critically affects their functions which is well exemplified by antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis mediated by homologous FcγRIIIa and FcγRIIIb, respectively. Although several reports describe N-glycosylation profiles of recombinant FcγRIII glycoproteins, much remains unknown regarding their native glycoforms.

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The complement system is a key component of the innate immunity, playing a role in pathogen elimination and in host homeostasis. The complement system has been considered for long time as an anti-tumoral element. However, recent studies showed a pro-tumoral effect of complement and particularly of the anaphylatoxines C3a and C5a in a large variety of tumor types.

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Prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy are at higher risk of tumor recurrence and receive immediate androgen deprivation therapy (ADT). While approximately 30% of these patients do not experience recurrence, others experience disease recurrence despite ADT, and currently no biomarkers can accurately identify them. We analyzed tumors from 51 patients with node-positive prostate cancer using immunohistochemistry to investigate whether expression of the immune checkpoint ligand PD-L1 by tumor cells or the density of CD8 or CD20 cells are associated with clinical progression.

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Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that reflect lymphoid neogenesis occurring in tissues at sites of inflammation. They are detected in tumors where they orchestrate local and systemic anti-tumor responses. A correlation has been found between high densities of TLS and prolonged patient's survival in more than 10 different types of cancer.

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