Showing papers by "Wolf H. Fridman published in 2020"

B cells and tertiary lymphoid structures promote immunotherapy response

Abstract: Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

B cells are associated with survival and immunotherapy response in sarcoma.

Abstract: Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases. Immune profiling of the tumour microenvironment of soft-tissue sarcoma identifies a group of patients with high levels of B-cell infiltration and tertiary lymphoid structures that have improved survival and a high response rate to immune checkpoint blockade therapy.

The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies.

Abstract: Tumor cells constantly interact with their microenvironment, which comprises a variety of immune cells together with endothelial cells and fibroblasts. The composition of the tumor microenvironment (TME) has been shown to influence response to immune checkpoint blockade (ICB). ICB takes advantage of immune cell infiltration in the tumor to reinvigorate an efficacious antitumoral immune response. In addition to tumor cell intrinsic biomarkers, increasing data pinpoint the importance of the TME in guiding patient selection and combination therapies. Here, we review recent efforts in determining how various components of the TME can influence response and resistance to ICB. Although a large body of evidence points to the extent and functional orientation of the T cell infiltrate as important in therapy response, recent studies also confirm a role for other components of the TME, such as B cells, myeloid lineage cells, cancer-associated fibroblasts, and vasculature. If the ultimate goal of curative cancer therapies is to induce a long-term memory T cell response, the other components of the TME may positively or negatively modulate the induction of efficient antitumor immunity. The emergence of novel high-throughput methods for analyzing the TME, including transcriptomics, has allowed tremendous developments in the field, with the expansion of patient cohorts, and the identification of TME-based markers of therapy response. Together, these studies open the possibility of including TME-based markers for selecting patients that are likely to respond to specific therapies, and pave the way to personalized medicine in oncology.

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint.

Abstract: 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. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.

The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression.

Abstract: Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases. While numerous methods can quantify immune or stromal cells in human tissue samples from transcriptomic data, few are available for mouse studies. We introduce murine Microenvironment Cell Population counter (mMCP-counter), a method based on highly specific transcriptomic markers that accurately quantify 16 immune and stromal murine cell populations. We validated mMCP-counter with flow cytometry data and showed that mMCP-counter outperforms existing methods. We showed that mMCP-counter scores are predictive of response to immune checkpoint blockade in cancer mouse models and identify early immune impacts of Alzheimer’s disease.

Complement System: Promoter or Suppressor of Cancer Progression?

Abstract: Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.

Early Hepatic Lesions Display Immature Tertiary Lymphoid Structures and Show Elevated Expression of Immune Inhibitory and Immunosuppressive Molecules.

Abstract: Purpose: The impact of tertiary lymphoid structures (TLS) in hepatocellular carcinoma (HCC) progression is being extensively investigated. However, their presence during the early steps of human liver carcinogenesis remains unknown. We thus aimed to determine whether TLS are induced in preneoplastic/early hepatic lesions, and if they are associated with a particular immune profile. Experimental Design: A series of 127 early hepatic lesions (EHL) (low/high grade dysplastic nodules, early HCC and small and progressed HCC) was included in the study. TLS were investigated by pathological reviewing. Densities of immune cells were assessed using immunohistochemistry. A subset of lesions was microdissected and gene expression profiling was performed with a custom Nanostring panel. Results: Compared to surrounding cirrhotic nodules, EHL of all stages displayed increased densities of T cells, B cells and dendritic cells. Immature Tertiary lymphoid structures (TLS) were identified in 24% of EHL. Gene expression profiling identified a subset of EHL with elevated mRNA levels of various cytokines involved in immune cells recruitment and TLS induction. This subgroup of EHL also showed overexpression of genes related to T and B cells activation and antigen presentation as well as those related to immunosuppression and immune exhaustion. Conclusions: Local immune activation occurs in the very early steps of liver carcinogenesis, however it may not be fully efficient and paradoxically favor immune evasion and progression to full-blown HCC. These results have implications for the development of anti-HCC chemo-preventive strategies in cirrhotic patients.

NIVOREN GETUG-AFU 26 translational study: Association of PD-1, AXL, and PBRM-1 with outcomes in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) treated with nivolumab (N).

Abstract: 618Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of N in mccRCC pts in a “real world setting”. A translationnal research program was launched to characterize immune cell p...

webMCP-counter: a web interface for transcriptomics-based quantification of immune and stromal cells in heterogeneous human or murine samples

Abstract: Summary We previously reported MCP-counter and mMCP-counter, methods that allow precise estimation of the immune and stromal composition of human and murine samples from bulk transcriptomic data, but they were only distributed as R packages. Here, we report webMCP-counter, a user-friendly web interface to allow all users to use these methods, regardless of their proficiency in the R programming language. Availability and Implementation Freely available from http://134.157.229.105:3838/webMCP/. Website developed with the R package shiny. Source code available from GitHub: https://github.com/FPetitprez/webMCP-counter.

The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression

Abstract: Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases, notably cancer. While numerous methods allow to quantify immune or stromal cells in human tissue samples based on transcriptomic data, very few are available for mouse studies. Here, we introduce murine Microenvironment Cell Population counter (mMCP-counter), a method based on highly specific transcriptomic markers that allow to accurately quantify 12 immune and 4 stromal murine cell populations. We validated mMCP-counter with flow cytometry data. We also showed that mMCP-counter outperforms existing methods. We showed in mouse models of mesothelioma and kidney cancer that mMCP-counter quantification scores are predictive of response to immune checkpoint blockade Finally, we illustrated mMCP-counter’s potential to analyze immune impacts of Alzheimer’s disease. mMCP-counter is available as an R package from GitHub: https://github.com/cit-bioinfo/mMCP-counter.