Muhammad Zaeem Noman

Muhammad Zaeem Noman
LIH Luxembourg Institute of Health | CRP Santé · Department of Oncology

DVM, MS, PhD

About

74
Publications
18,144
Reads
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5,330
Citations
Additional affiliations
April 2006 - June 2016
Institut de Cancérologie Gustave Roussy
Position
  • PostDoc Position

Publications

Publications (74)
Article
Novel approaches to reduce tumor immunosuppression and improve responses to anti-cancer immunotherapies based on immune-checkpoint inhibitors are needed. Emerging evidence demonstrates that autophagy inhibition enhances anti-tumor immunity by tumor cell-intrinsic and extrinsic mechanisms. Recently, we reported that pharmacological inhibition of VPS...
Article
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Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions are still poorly understood. Here we show that antifolate treatment res...
Article
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Hypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiti...
Preprint
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Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs mainly target the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Thus, we aimed to identify metabolic determinants that...
Preprint
Full-text available
Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs target mainly the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Thus, we aimed to identify metabolic determinants that...
Article
Full-text available
CMTM6 is a critical regulator of cell surface expression of PD-L1 in tumor cells, but little is known about the transcriptional regulation of CMTM6. Here we report that the expression of CMTM6 positively correlates with the epithelial to mesenchymal transition (EMT) score in breast cancer cell lines and with the major EMT marker Vimentin in triple-...
Article
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Atypical chemokine receptors (ACKRs) are important regulators of chemokine functions. Among them, the atypical chemokine receptor ACKR2 (also known as D6) has long been considered as a scavenger of inflammatory chemokines exclusively from the CC family. In this study, by using highly sensitive β-arrestin recruitment assays based on NanoBiT and Nano...
Article
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Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our unde...
Article
AC BioScience is a Swiss biotech company based at the EPFL Innovation Park and Biopôle, dedicated to developing groundbreaking therapies to fight a range of cancers and infectious diseases. We are about to start clinical trials with two of four leading-edge cancer drugs mainly focusing on immune-oncology and tumor vascular normalization with multi-...
Article
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Cancer immunotherapy based on Immune checkpoint blockade (ICB) is a promising strategy to treat patients with advanced highly aggressive therapy-resistant tumors. Unfortunately, the clinical reality is that only a small number of patients benefit from the remarkable clinical remissions achieved by ICB. Experimental and clinical evidence claimed tha...
Article
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Cancer immunotherapy based on anti-PD-1/PD-L1 blockade is particularly effective in responding to patients with hot tumors. These tumors are characterized by the accumulation of proinflammatory cytokines and T cell infiltration. In our recent report published in Science Advances, we demonstrate that targeting the autophagy-related protein Vps34 swi...
Article
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One of the major challenges limiting the efficacy of anti–PD-1/PD-L1 therapy in nonresponding patients is the failure of T cells to penetrate the tumor microenvironment. We showed that genetic or pharmacological inhibition of Vps34 kinase activity using SB02024 or SAR405 (Vps34i) decreased the tumor growth and improved mice survival in multiple tum...
Chapter
Macroautophagy (hereafter referred to as autophagy) is a cellular degradation process involved in the recycling of damaged organelles and proteins. Occurring at the basal level, autophagy participates in maintaining homeostasis in all cells. Deregulation in this process is observed in several pathologies such as cancer. Autophagy plays a dual role...
Article
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Initially believed to be a disease of deregulated cellular and genetic expression, cancer is now also considered a disease of the tumor microenvironment. Over the past two decades, significant and rapid progress has been made to understand the complexity of the tumor microenvironment and its contribution to shaping the response to various anti-canc...
Article
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First thought to orchestrate exclusively leukocyte trafficking, chemokines are now acknowledged for their multiple roles in the regulation of cell proliferation, differentiation, and survival. Dysregulation of their normal functions contributes to various pathologies, including inflammatory diseases and cancer. The two chemokine receptor 3 variants...
Article
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Compared to traditional therapies, such as surgery, radio-chemotherapy, or targeted approaches, immunotherapies based on immune checkpoint blockers (ICBs) have revolutionized the treatment of cancer. Although ICBs have yielded long-lasting results and have improved patient survival, this success has been seriously challenged by clinical observation...
Article
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Natural Killer (NK) cell-based cancer immunotherapies were often disappointing in the clinic mostly due to insufficient NK cell infiltration into tumors. We found that targeting autophagy induced a massive infiltration of NK cells into melanoma tumors. These findings highlight autophagy inhibition as a cutting-edge approach to fully exploit the ant...
Article
Solid tumors are able to establish and sustain an immune suppressive microenvironment, which prevents the infiltration of cytotoxic effector immune cells into the tumor bed. We showed that genetic targeting of the macroautophagy/autophagy gene Becn1/Beclin1 in B16-F10 tumors inhibits their growth by inducing a massive infiltration of functional nat...
Article
Autophagy is a quality control process executed at the basal level in almost all cell types. However, in cancer cells, autophagy is activated by several stimuli, including hypoxia. Depending on tumor type, stage, and genetic context, autophagy is a double-edged sword. Autophagy promotes regression in newly established tumors; however, it supports t...
Article
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Gradients of hypoxia occur in most solid tumors and cells found in hypoxic regions are associated with the most aggressive and therapy-resistant fractions of the tumor. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia in melanoma. Using microarray technol...
Article
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While blocking tumor growth by targeting autophagy is well established, its role on the infiltration of natural killer (NK) cells into tumors remains unknown. Here, we investigate the impact of targeting autophagy gene Beclin1 (BECN1) on the infiltration of NK cells into melanomas. We show that, in addition to inhibiting tumor growth, targeting BEC...
Article
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We report that CD47 was up-regulated in different EMT-activated human breast cancer cells versus epithelial MCF7 cells. Overexpression of SNAI1 or ZEB1 in epithelial MCF7 cells activated EMT and upregulated CD47 while siRNA-mediated targeting of SNAI1 or ZEB1 in mesenchymal MDA-MB-231 cells reversed EMT and strongly decreased CD47. Mechanistically,...
Article
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Tumor escape to immunosurveillance and resistance to immune attacks present a major hurdle in cancer therapy, especially in the current era of new cancer immunotherapies. We report here that hypoxia, a hallmark of most solid tumors, orchestrates carcinoma cell heterogeneity through the induction of phenotypic diversity and the acquisition of distin...
Article
Hypoxia upregulates the core pluripotency factors NANOG, SOX2, and OCT4, associated with tumor aggressiveness and resistance to conventional anticancer treatments. We have previously reported that hypoxia-induced NANOG contributed in vitro to tumor cell resistance to autologous-specific CTL and in vivo to the in situ recruitment of immune-suppressi...
Article
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PD-L1 expression and regulation by mesenchymal tumor cells remain largely undefined. Here, we report that among different EMT-activated MCF7 human breast cancer cell clones, PD-L1 was differentially upregulated in MCF7 sh-WISP2, MCF7–1001/2101, and MDA-MB-231 cells but not in MCF7 SNAI1 and MCF7 SNAI1–6SA cells. Mechanistic investigations revealed...
Article
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Macroautophagy (hereafter referred to as autophagy) is a housekeeping process constitutively executed at basal level in all cells to promote cellular homeostasis by regulating organelle and protein turnover. However, autophagy deregulation caused by several stress factors, such as hypoxia, is prevalent in many cancers. It is now well established th...
Article
Tumors use several strategies to evade the host immune response, including creation of an immune-suppressive and hostile tumor environment. Tissue hypoxia due to inadequate blood supply is reported to develop very early during tumor establishment. Hypoxic stress has a strong impact on tumor cell biology. In particular, tissue hypoxia contributes to...
Article
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It is well recognized that the immune system and metabolism are highly integrated. In this context, multilevel interactions between metabolic system and T lymphocyte signaling and fate exist. This review will discuss different potential cell metabolism pathways involved in shaping T lymphocyte function and differentiation. We will also provide a ge...
Article
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While autophagy is constitutively executed at basal level in all cells, it is activated in cancer cells in response to various microenvironmental stresses including hypoxia. It is now well established that autophagy can act both as tumor suppressor or tumor promoter. In this regard, several reports indicate that the tumor suppressor function of aut...
Article
Background: Clear cell renal cell carcinomas (ccRCC) frequently display a loss of function of the von Hippel-Lindau (VHL) gene. Objective: To elucidate the putative relationship between VHL mutation status and immune checkpoint ligand programmed death-ligand 1 (PD-L1) expression. Design, setting, and participants: A series of 32 renal tumors c...
Article
It has become clear that tumor stroma components are engaged in an active and complex molecular cross-talk that has serious implications for immunological recognition of tumor cells in shaping the microenvironment. Hypoxia which is a major component of tumor microenvironment influences the characteristics of neoplasia by favoring heterogeneity, inv...
Article
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Blurring the boundary between innate and adaptive immune system, natural killer (NK) cells, a key component of the innate immunity, are recognized as potent anticancer mediators. Extensive studies have been detailed on how NK cells get activated and recognize cancer cells. In contrast, few studies have been focused on how tumor microenvironment-med...
Article
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The tumor microenvironment is a complex system playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. This review outlines the potential role of hypoxia, a major feature of most solid tumors, within tumor microenvir...
Article
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Myeloid Derived Suppressor Cells (MDSCs) are an integral component of the hypoxic tumor microenvironment. We demonstrated that hypoxia selectively induced miR-210 via HIF-1α in splenic MDSCs from tumor-bearing mice. Overexpression of miR-210 enhanced MDSC-mediated T c...
Article
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Although natural killer cells (NK) play an important role in the control of melanoma, hypoxic stress in the tumor microenvironment may impair NK- mediated tumor cell killing by mechanisms which are not fully understood. In this study, we investigated the effect of hypoxia on the expression and the channel activity of connexin-43 (Cx43) in melanoma...
Article
Myeloid derived suppressor cells (MDSC) contribute significantly to the malignant characters conferred by hypoxic tumor microenvironments. However, selective biomarkers of MDSC function in this critical setting have not been defined. Here we report that miR-210 expression is elevated by HIF-1α in MDSC localized to tumors, compared to splenic MDSC f...
Article
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Tumor-derived microvesicles (TD-MVs) are key mediators which are shed by cancer cells and can sensitize neighboring cells in the tumor microenvironment. TD-MVs are extracellular vesicles composed of exosomes and MVs and promote cancer invasion and metastasis. Intratumoral hypoxia is an integral component of all solid tumors. The relationship betwee...
Article
417 Background: Clear cell renal cell carcinomas frequently display inactivation of VHL gene leading to increased level of hypoxia inducible factors (HIFs). The specific role of VHL mutations and selective activation of HIF-2 alpha in modulating RCC susceptibility to cytotoxic immune response remains largely unknown. Methods: In this study, we used...
Article
Clear cell renal cell carcinoma (ccRCC) is dominated by inactivating mutations in VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase), leading to constitutive activation of the hypoxia-inducible factors (HIFs) and induction of a hypoxia response transcription signature. Our study demonstrated that VHL mutation results in the acqui...
Article
We recently investigated the role of von Hippel-Lindau (VHL) mutation and the subsequent induction of hypoxia-inducible factor 2α (HIF-2α) in the regulation of renal cell carcinoma (RCC) susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the resistance of VHL-mutated RCC cell line 786-0 to NK-mediated lysis requires H...
Article
Hypoxia influences immune checkpoint receptors and their respective ligands. In support, we recently demonstrated that hypoxia selectively upregulates programmed cell death ligand 1 (PD-L1) on myeloid-derived suppressor cells (MDSCs) via hypoxia inducible factor 1 alpha (HIF-1 alpha) binding to a hypoxia-response element (HRE) in the PD-L1 proximal...
Chapter
The tumor microenvironment (TME) promotes neoplastic transformation, supports tumor growth and invasion, protects the tumor from host immunity and fosters therapeutic resistance. It is well established that tumor stroma components are engaged in an active and complex molecular cross-talk that has serious implications for immunological recognition o...
Article
Full-text available
Accumulating evidence indicate that the behavior of tumorigenic cells is highly influenced by their microenvironment. In this regard, microenvironmental hypoxia plays a determinant role in the emergence of CTC (circulating tumor cells) and CSC (cancer stem cells). CTCs are believed to be indicators of residual disease and thus pose an increased ris...
Article
Full-text available
Clear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia inducible factors (HIFs). In this study, we investigated the potential role of HIF-2α in regulating RCC susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the RCC cell line 786-0...
Article
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Natural killer (NK) cells are effectors of the innate immune system, able to kill cancer cells through the release of the cytotoxic protease granzyme B. NK-based therapies have recently emerged as promising anticancer strategies. However, it is well established that hypoxic tumo...
Article
Full-text available
Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [P...
Article
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The diversity of functional phenotypes observed within a tumor does not exclusively result from intratumoral genetic heterogeneity but also from the response of cancer cells to the microenvironment. We have previously demonstrated that the morphological and functional phenotypes of melanoma can be dynamically altered upon external stimuli. In the p...
Article
Hypoxia is a major feature of most solid tumors. Cells adapt to lower oxygen availability by stabilizing HIF transcription factors, which in turn activate the expression of many genes resulting in the survival and maintenance of cellular functions. In tumor cells, exposure to hypoxic stress results in the activation, via the HIF factors, of a serie...
Article
A previously undescribed and robust miR210 overexpression is shown in intestinal samples obtained from patients with radiation enteropathy and fibrotic cultured cells. In addition, miR-210 overexpression is repressed by antifibrotic treatment combining pentoxifylline and α-tocopherol.
Article
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The crucial issue for defining successful natural killer (NK)-based anticancer therapy is the ability of tumor cells to activate resistance mechanisms leading to escape from NK-mediated killing. It is now well established that such mechanisms are likely evolved under hypoxia in the tumor microenvironment. Here, we show that hypoxia-induced autophag...
Article
Full-text available
Emerging evidence suggests a link between tumor hypoxia and immune suppression. In this study, we investigated the role of hypoxia-induced Nanog, a stemness-associated transcription factor, in immune suppression. We observed that hypoxia-induced Nanog correlated with the acquisition of stem cell-like properties in B16-F10 cells. We further show tha...
Article
Recent studies demonstrated that autophagy is an important regulator of innate immune response. However, the mechanism by which autophagy regulates natural killer (NK) cell-mediated antitumor immune responses remains elusive. Here, we demonstrate that hypoxia impairs breast cancer cell susceptibility to NK-mediated lysis in vitro via the activation...
Article
Full-text available
Unlabelled: Gap junctions (GJs) enable intercellular communication between adjacent cells through channels of connexins. Using a three-dimensional construct, we previously showed that endothelial and tumor cells formed GJs, allowing melanoma-specific T lymphocytes to recognize and kill melanoma-derived endothelial cells. We demonstrate here on his...
Article
Epithelial to mesenchymal transition (EMT) has become one of the most exciting fields in cancer biology. While its role in cancer cell invasion, metastasis and drug resistance is well established, the molecular basis of EMT-induced immune escape remains unknown. We recently reported that EMT coordinately regulates target cell recognition and sensit...
Article
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Epithelial-to-mesenchymal transition (EMT) mediates cancer cell invasion, metastasis and drug resistance, but its impact on immune surveillance has not been explored. In this study, we investigated the functional consequences of this mode of epithelial cell plasticity on targeted cell lysis by cytotoxic T lymphocytes (CTL). Acquisition of the EMT p...
Article
Hypoxia is a common feature of solid tumors and one of the hallmarks of tumor microenvironment. Tumor hypoxia plays an important role in angiogenesis, malignant progression, metastatic development, chemo-radio resistance and favours immune evasion by the emergence of tumor variants with increased survival and anti-apoptotic potential. There is very...
Article
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Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lym...
Article
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A major challenge in formulating an effective immunotherapy is to overcome the mechanisms of tumor escape from immunosurveillance. We showed that hypoxia-induced autophagy impairs cytotoxic T-lymphocyte (CTL)-mediated tumor cell lysis by regulating phospho-STAT3 in target cells. Autophagy inhibition in hypoxic cells decreases phospho-STAT3 and rest...