Salem Chouaib

• PhD
• Managing Director at Institut Gustave Roussy

Background: Advancing chimeric antigen receptor (CAR) T cell therapy for solid tumors remains a major challenge in cancer immunotherapy. Prostate cancer (PCa), particularly in its aggressive forms, may be a suitable target for CAR-T therapy given the range of associated tumor antigens. However, due to the high plasticity and heterogeneity of aggres...

Hypoxia is known to induce reprogramming of glucose metabolism in cancer. However, the impact of hypoxia on global metabolism remains poorly understood. Here, using the systems approach, we evaluated the potential crosstalk between hypoxia and global metabolism using data from > 2000 breast tumors. Tumor samples were scored for hypoxia and 90 metab...

Pancreatic cancer mostly manifests as pancreatic ductal adenocarcinoma (PDAC) and is characterized by a highly hypoxic microenvironment that is associated with worse patient survival and resistance to therapy. Hypoxia induces angiogenesis and the resulting leaky and unstructured vessels fail to reoxygenate the tumor mass, thus exacerbating hypoxia...

Simple Summary Mutations of the von Hippel–Lindau (VHL) gene lead to VHL disease in patients. It is characterized by numerous benign and malignant tumors in different organs, as highly vascularized clear cell renal cell carcinomas (ccRCCs). The aim of this study was to examine the consequences of VHL-C162F mutation on morphology, proliferation, abi...

The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hyp...

Background Melanoma is a lethal skin cancer, and the risk of developing it is increased by exposure to ultraviolet (UV) radiation. The production of cytokines such as interleukin-15 (IL-15), induced by the exposure of skin cells to UV rays, could also promote melanoma development. The aim of this study is to investigate the possible role of Interle...

4548 Background: Antibiotics (ATB) deviate the gut taxonomic microbiota composition and have a deleterious impact on survival in ICI-treated pts. ATB downregulate the ileal mucosal addressin cell adhesion molecule-1 (MAdCAM-1), leading to the recirculation of immunosuppressive enterotropic T cells into the tumor and ICI resistance. Here, we aimed t...

Hypoxia afflicts the microenvironment of solid tumors fueling malignancy. We investigated the impact of long hypoxia exposure on transcriptional remodeling, tumor mutational burden (TMB), and genomic instability of cancer cells that were grouped based on their inherent sensitivity or resistance to hypoxia. A hypoxia score was used as a metric to di...

724 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes and irAEs in mRCC pts treated with nivolumab. We previously identified (training-set = 80 pts, validation-set= 233 pts) several soluble factors associated with overall surv...

Simple Summary Hypoxia is a key feature of the tumor microenvironment involved in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC). In this review we will highlight hypoxia’s integral role in shaping genomic instability and the tumor immune microenvironment in this disease. We will further present strategies currently being investigated...

The recent trend in 3D cell modeling has fostered the emergence of a wide range of models, addressing very distinct goals ranging from the fundamental exploration of cell–cell interactions to preclinical assays for personalized medicine. It is clear that no single model will recapitulate the complexity and dynamics of in vivo situations. The key is...

Almost all solid tumors display hypoxic areas in the tumor microenvironment associated with therapeutic failure. It is now well established that the abnormal growth of malignant solid tumors exacerbates their susceptibility to hypoxia. Therefore, targeting hypoxia remains an attractive strategy to sensitize tumors to various therapies. Tumor cell a...

The role of autophagy in lung cancer cells exposed to waterpipe smoke (WPS) is not known. Because of the important role of autophagy in tumor resistance and progression, we investigated its relationship with WP smoking. We first showed that WPS activated autophagy, as reflected by LC3 processing, in lung cancer cell lines. The autophagy response in...

Smoking is the number one risk factor for lung cancer and tobacco smokers are at 20 to 40 times higher risk of developing lung cancer in comparison to non-smokers. We have previously shown that exposing lung cancer cell lines to tobacco smoke condensate generated from waterpipe (WP) interferes with cell proliferation, cell plasticity, DNA damage an...

Hypoxia afflicts the microenvironment of solid tumors fueling tumor malignancy. Using an 8-gene in vitro hypoxia signature, we have recently shown that pancreatic cancer patients with highly hypoxic tumors experience worse survival and exhibit markers of an immunosuppressed microenvironment. Simultaneously, we obtained evidence of increased mutatio...

4552 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes to nivolumab in mRCC pts. We previously identified on a training set (n = 80, 40 responders/40 progressors) several soluble factors significantly associated with worse ove...

Background The phase II NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) in a ‘real-world setting’. We conducted a translational-research program to determine whether specific circulating immune-cell populations and/or soluble factors at baseline were predicti...

The development and implementation of Immune Checkpoint Inhibitors (ICI) in clinical oncology have significantly improved the survival of a subset of cancer patients with metastatic disease previously considered uniformly lethal. However, the low response rates and the low number of patients with durable clinical responses remain major concerns and...

Background Cancer stem cells (CSC) define a population of rare malignant cells endowed with ‘stemness’ properties, such as self-renewing, multipotency and tumorigenicity. They are responsible for tumor initiation and progression, and could be associated with resistance to immunotherapies by negatively regulating antitumor immune response and acquir...

Pharmacological reactivation of tumor‑suppressor protein p53 has acted as a promising strategy for more than 50% of human cancers that carry a non‑functional mutant p53 (mutp53). p53 plays a critical role in preserving genomic integrity and DNA fidelity through numerous biological processes, including cell cycle arrest, DNA repair, senescence and a...

379 Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with RCC in a “real world setting”. A translational research program was launched to quantify baseline cytokine levels and correlate them with outcomes to nivolumab. Methods: Extreme responder patients (pts) treated with nivolumab as part of the pha...

Hypoxia is an environmental stressor that is instigated by low oxygen availability. It fuels the progression of solid tumors by driving tumor plasticity, heterogeneity, stemness and genomic instability. Hypoxia metabolically reprograms the tumor microenvironment (TME), adding insult to injury to the acidic, nutrient deprived and poorly vascularized...

Tumor-associated macrophages (TAM) plasticity and diversity are both essential hallmarks of the monocyte-macrophage lineage and the tumor-derived inflammation. TAM exemplify the perfect adaptable cell with dynamic phenotypic modifications that reflect changes in their functional polarization status. Under several tumor microenvironment (TME)-relate...

Purpose: A minority of patients currently respond to single agent immune checkpoint blockade (ICB) and strategies to increase response rates are urgently needed. AXL is receptor tyrosine kinase commonly associated with drug-resistance and poor prognosis in many cancer types including in clear-cell renal cell carcinoma (ccRCC). Recent experimental...

Von Hippel–Lindau disease (VHL) is a rare hereditary syndrome due to mutations of the VHL tumor suppressor gene. Patients harboring the R167Q mutation of the VHL gene have a high risk of developing ccRCCs. We asked whether the R167Q mutation with critical aspects of pseudo-hypoxia interferes with tumor plasticity. For this purpose, we used wild-typ...

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...

Evading the immune system is one of the hallmarks of cancer. Tumors escape anti-tumor immunity through cell-intrinsic means and the assembly of an immunosuppressive tumor microenvironment. By significantly boosting the host immune system, cancer immunotherapies targeting immune checkpoint receptors (CTLA-4 and PD-1) improved survival in patients ev...

Intratumoral hypoxia is a widely established element of the pancreatic tumor microenvironment (TME) promoting immune escape, tumor invasion, and progression, while contributing to treatment resistance and poor survival. Despite this critical role, hypoxia is underrepresented in molecular signatures of pancreatic ductal adenocarcinoma (PDA) and conc...

Simple Summary Autophagy is a self-eating mechanism that is involved in the degradation of organelles and cellular materials. It is initiated by intracellular and extracellular stress stimuli. In the context of tumor development, microenvironmental hypoxic stress regulates autophagy that, in turn, promotes cancer-cell death or cancer-cell survival....

The environmental and metabolic pressures in the tumor microenvironment (TME) play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition and activation. Hypoxia triggers a cascade of events that promote tumor growth, enhance resistance to the anti-tumor immune response and instigate tumor angiog...

Waterpipe tobacco smoking (WPS) continues to spread globally and presents serious health hazards. The aim of the present study was to investigate the effects of treatment with WPS condensate (WPSC) on lung cell proliferation and plasticity as well as tumor cell recognition and killing by natural killer (NK) cells using cytotoxicity assays. The resu...

Cancer-associated fibroblasts (CAFs) and hypoxia are central players in the complex process of tumor cell-stroma interaction and are involved in the alteration of the anti-tumor immune response by impacting both cancer and immune cell populations. However, even if their independent immunomodulatory properties are now well documented, whether the in...

We recently reported that inhibiting Hypoxia-inducible Factor-1α (Hif1a) transcriptional activity improves melanoma immunotherapy by driving immune cells into the tumor microenvironment (TME). This Author’s View provides additional perspectives on how hypoxia inhibitors combined with immunotherapy can be used as innovative approaches to improve the...

Resistance of tumor cells to cell‑mediated cytotoxicity remains an obstacle to the immunotherapy of cancer and its molecular basis is poorly understood. To investigate the acquisition of tumor resistance to cell‑mediated cytotoxicity, resistant variants were selected following long‑term natural killer (NK) cell selection pressure. It was observed t...

Epithelial-mesenchymal plasticity (EMP) of cancer cells contributes to cancer cell heterogeneity, and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy, chemotherapy, and targeted therapies. Here, we aimed to explore how EMP contributes to cancer cell camoufla...

While it is widely accepted that high intratumoral heterogeneity confers serious challenges in the emerging resistance and the subsequent effective therapeutic targeting of cancer, the underlying biology of intratumoral heterogeneity remains elusive. In particular, it remains to be fully elucidated how microenvironmental factors shape genetic and n...

Tumor hypoxia has long been considered as a driving force of tumor progression and to play a key role in remodeling the tumor stroma and favoring the emergence of tolerance. The receptor tyrosine kinase AXL is associated with drug resistance in several solid tumors and AXL-targeting agents are currently in clinical trials. We investigated the relat...

Tumor hypoxia-induced downregulation of DNA repair pathways and enhanced replication stress are potential sources of genomic instability. A plethora of genetic changes such as point mutations, large deletions and duplications, microsatellite and chromosomal instability have been discovered in cells under hypoxic stress. However, the influence of hy...

618 Background: 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 populations in the tumor by immunohistochemistry (IHC) and correlate them with outcome on N. Methods: All pts treated with N in the GETUG AFU 26 NIVOREN...

Introduction: Acquired cancer therapy resistance evolves under selection pressure of immune surveillance and favors mechanisms that promote drug resistance through cell survival and immune evasion. AXL receptor tyrosine kinase is a mediator of cancer cell phenotypic plasticity and suppression of tumor immunity, and AXL expression is associated wit...

Immunotherapy is poised to become an increasingly utilized therapy in the treatment of cancer. However, several abnormalities in the tumor microenvironment (TME) that can thwart the efficacy of immunotherapies have been established. Microenvironmental hypoxia is a determining factor in shaping aggressiveness, metastatic potential and treatment resi...

The immune system is a potent defense mechanism regulating tumor development and progression. The ultimate goal of cancer immunotherapy is to eradicate malignant cells through the cytotoxic machinery of immune cells such as cytotoxic T cells (CTLs) and Natural killer (NK) cells. However, the killing potential of these cells is often dampened by the...

Autophagy has a multifaceted role in cancer, and a growing body of evidence demonstrates a central role for autophagy in modulating adjuvanticity, which is essential for natural and therapy-induced immunosurveillance. Adjuvanticity in this context is conferred by the release of specific damage associated molecular patterns (DAMPs) from dying cancer...

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...

Immune resistance may arise from both genetic instability and tumor heterogeneity. Microenvironmental stresses such as hypoxia and various resistance mechanisms promote carcinoma cell plasticity. AXL, a member of the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase family, is widely expressed in human cancers and increasingly recognized for its r...

Cytotoxic T lymphocytes (CTL) and natural killer cells (NK)-mediated elimination of tumor cells is mostly dependent on Granzyme B apoptotic pathway, which is regulated by the wild type (wt) p53 protein. Because TP53 inactivating mutations, frequently found in human tumors, could interfere with Granzyme B-mediated cell death, the use of small molecu...

Transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers and promotes uncontrolled tumor growth and progression through multiple mechanisms. Compelling evidence shows tissue and cell-specific sets of STAT3 targets. Transcriptional targets of STAT3 in melanoma cells are largely unkno...

Recent advances in lung cancer treatment are emerging from new immunotherapies that target T-cell inhibitory receptors, such as programmed cell death-1 (PD-1). However, responses to anti-PD-1 antibodies as single agents are observed in fewer than 20% of non-small-cell lung cancer (NSCLC) patients, and immune mechanisms involved in the response to t...

Recent antitumor immunotherapies such as monoclonal antibodies targeting immune checkpoints have led to outstanding results in several cancers. However, despite the favorable outcomes for responding patients, the response rate remains relatively low. This is in part due to the influence of the tumor microenvironment (TME) in protecting the tumor fr...

Tumours often evade CD8 T-cell immunity by downregulating TAP. T-cell epitopes associated with impaired peptide processing are immunogenic non-mutated neoantigens that emerge during tumour immune evasion. The preprocalcitonin (ppCT)16–25 neoepitope belongs to this category of antigens. Here we show that most human lung tumours display altered expre...

Hypoxia, or gradients of hypoxia, occurs in most growing solid tumors and may result in pleotropic effects contributing significantly to tumor aggressiveness and therapy resistance. Indeed, the generated hypoxic stress has a strong impact on tumor cell biology. For example, it may contribute to increasing tumor heterogeneity, help cells gain new fu...

Elucidation of the underlying molecular mechanisms of immune evasion in cancer is critical for the development of immunotherapies aimed to restore and stimulate effective antitumor immunity. Here, we evaluate the role of the actin cytoskeleton in breast cancer cell resistance to cytotoxic natural killer (NK) cells. A significant fraction of breast...

Backgound: Hypoxia is known to shape the tumor microenvironment of developing tumors and contributes to both tumor progression and escape to immune surveillance. Previous work using non-small cell lung carcinoma cells (NSCLC) showed that hypoxia promotes epithelial-mesenchymal transition (EMT) in a fraction of carcinoma cells and that acquisition o...

The AXL receptor tyrosine kinase is associated with poor overall survival in a wide spectrum of cancers. AXL signaling is important for tumor cell plasticity related to epithelial-to-mesenchymal transition (EMT), immune escape and intrinsic resistance to cytotoxic lymphocytes. AXL is expressed on several cells associated with the tumor immune micro...

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with very few available treatments. For many decades, gemcitabine was the only treatment for patients with PDAC. A recent attempt to improve patient survival by combining this chemotherapy with FOLFIRINOX and nab-paclitaxel failed and instead resulted in increa...

Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment...

Among cells present in the tumor microenvironment, activated fibroblasts termed cancer-associated fibroblasts (CAFs), play a critical role in the complex process of tumor-stroma interaction. CAFs, one of the prominent stromal cell populations in most types of human carcinomas, have been involved in tumor growth, angiogenesis, cancer stemness, extra...

Hypoxia characterizes growing tumors and contributes significantly to their aggressiveness. Hypoxia-inducible factors (HIFs 1 and 2) are stabilized and act differentially as transcription factors on tumor growth and are responsible for important cancer hallmarks such as pathologic angiogenesis, cellular proliferation, apoptosis, differentiation and...

Background. The AXL receptor tyrosine kinase is associated with poor overall survival in breast cancer. AXL signaling is an important regulator of tumor plasticity related to epithelial-to-mesenchymal transition (EMT) and stem cell traits that drive metastasis and drug resistance. Upregulation of AXL has been associated with reduced response to ant...

TPS43 Background: Activation of the receptor tyrosine kinase AXL has a profound suppressive effect on the innate immune system. AXL is overexpressed on multiple cell types in the tumour immune microenvironment including dendritic cells, NK cells and tumour-associated macrophages. AXL signalling in immune cells supports tumour immune escape by downr...

The microenvironment of a developing tumor is composed of proliferating cancer cells, blood vessels, stromal cells, infiltrating inflammatory cells, and a variety of associated tissue cells. The crosstalk between stromal cells and malignant cells within this environment crucially determines the fate of tumor progression, its hostility, and heteroge...

Adoptive transfer of allogeneic natural killer (NK) cells represents a promising treatment approach against acute myeloid leukemia (AML). We developed a cytokine-based culture method for the generation of NK cells derived from CD34+hematopoietic progenitor cells (HPC) isolated from fresh umbilical cord blood (UCB). Immuno-phenotyping of ex vivo exp...

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...

Significance The failure in achieving a durable clinical immune response against cancer cells depends on the ability of cancer cells to establish a microenvironment that prevent cytotoxic immune cells to infiltrate tumors and kill cancer cells. Therefore, the key approach to achieving successful antitumor immune response is to harness strategies al...

Vγ9Vδ2 T cells are anti-tumor immune effectors of growing interest in cancer including Pancreatic Ductal Adenocarcinoma (PDAC), an especially aggressive cancer characterized by a hypoxic and nutrient-starved immunosuppressive microenvironment. Since Butyrophilin 3 A (BTN3 A) isoforms are critical activating molecules of Vγ9Vδ2 T cells, we set out t...

The administration of ex vivo-expanded Natural Killer (NK) cells in leukemia therapy is still challenging, in part due to the difficulty to generate in sufficient quantities fully mature and functional NK cells and Identification of surface markers indicative of NK maturation and functionality is therefore needed. Here, based on the analysis of sur...

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,...

The AXL receptor tyrosine kinase is associated with poor overall survival in a wide spectrum of cancers including lung and breast adenocarcinomas. AXL signaling is an important regulator of tumor plasticity related to epithelial-to-mesenchymal transition (EMT) and stem cell traits that drive metastasis and drug resistance. Signaling via AXL is also...

Novel immunotherapy approaches have provided durable remission in a significant number of cancer patients with cancers previously considered rapidly lethal. Nonetheless, the high degree of non-responders, and in some cases the emergence of resistance in patients who do initially respond, represents a significant challenge in the field of cancer imm...

9549 Background: Preclinical findings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD...

Podoplanin (PDPN), an O-glycosylated, transmembrane, mucin-type glycoprotein, is expressed by cancer associated fibroblasts (CAFs). In malignant transformation, PDPN is subjected to changes and its role is yet to be established. Here we show that it is involved in modulating the activity of the CCL21/CCR7 chemokine/receptor axis in a hypoxia-depend...

The immune system and metabolism are highly integrated and multilevel interactions between metabolic system and T lymphocyte signaling and fate exist. Accumulating evidence indicates that the regulation of nutrient uptake and utilization in T cells is critically important for the control of their differentiation and manipulating metabolic pathways...

Front Immunol. 2017 Mar 13;8:270.

Cancer-associated fibroblasts (CAFs) play a central role in the complex process of tumor-stroma interaction and promote tumor growth. Emerging evidences also suggest that these fibroblasts are involved in the alteration of the anti-tumor immune response by impacting several immune cell populations, especially through their secretion of pro-inflamma...

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...

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...

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...