Publications by authors named "Lisa Derosa"

64 Publications

Multifaceted modes of action of the anticancer probiotic Enterococcus hirae.

Cell Death Differ 2021 May 11. Epub 2021 May 11.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFNγ-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
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http://dx.doi.org/10.1038/s41418-021-00753-8DOI Listing
May 2021

Fecal microbiota transplantation: can it circumvent resistance to PD-1 blockade in melanoma?

Signal Transduct Target Ther 2021 May 8;6(1):178. Epub 2021 May 8.

Gustave Roussy Comprehensive Cancer Institute, Clinicobiome, Villejuif, France.

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http://dx.doi.org/10.1038/s41392-021-00585-5DOI Listing
May 2021

Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.

Cell Death Differ 2021 May 7. Epub 2021 May 7.

Gustave Roussy Cancer Center, Villejuif, France.

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
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http://dx.doi.org/10.1038/s41418-021-00784-1DOI Listing
May 2021

Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers.

Cell Death Dis 2021 03 11;12(3):258. Epub 2021 Mar 11.

Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, 94800, Villejuif, France.

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
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http://dx.doi.org/10.1038/s41419-021-03540-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948172PMC
March 2021

Oral administration of elevates systemic antiaging and anticancer metabolites.

Aging (Albany NY) 2021 03 2;13(5):6375-6405. Epub 2021 Mar 2.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

The presence of (Akk) in the human gut is associated with good health, leanness and fitness. Mouse experimentation has demonstrated positive effects for Akk, which counteracts aging, mediates antiobesity and antidiabetic effects, dampens inflammation and improves anticancer immunosurveillance. Clinical trials have confirmed antidiabetic effects for Akk. Here, we investigated the time-dependent effects of oral administration of Akk (which was live or pasteurized) and other bacteria to mice on the metabolome of the ileum, colon, liver and blood plasma. Metabolomics was performed by a combination of chromatographic and mass spectrometric methods, yielding a total of 1.637.227 measurements. Akk had major effects on metabolism, causing an increase in spermidine and other polyamines in the gut and in the liver. Pasteurized Akk (Akk-past) was more efficient than live Akk in elevating the intestinal concentrations of polyamines, short-chain fatty acids, 2-hydroxybutyrate, as well multiple bile acids, which also increased in the circulation. All these metabolites have previously been associated with human health, providing a biochemical basis for the beneficial effects of Akk.
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http://dx.doi.org/10.18632/aging.202739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993698PMC
March 2021

Immunodynamics of explanted human tumors for immuno-oncology.

EMBO Mol Med 2021 Jan 29;13(1):e12850. Epub 2020 Dec 29.

Institut Gustave Roussy, Villejuif, France.

Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.
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http://dx.doi.org/10.15252/emmm.202012850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799366PMC
January 2021

Identification of international metastatic renal cell carcinoma database consortium (IMDC) intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma.

Oncotarget 2020 Dec 8;11(49):4582-4592. Epub 2020 Dec 8.

Department of Medical Oncology, Institute Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Majority of patients with clear-cell renal cell carcinoma (ccRCC) at first line (1L) treatment are classified in the intermediate-risk (IR) subgroup according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score. As these patients have different prognosis, the aim of this study is to better characterize IR patients in order to better tailor the treatment. Retrospective analysis was performed from IGReCC (Institut Gustave Roussy Renal Cell Carcinoma) database. Overall survival (OS) was defined from start of 1L therapy to death or last follow-up. A multivariable Cox model with backward selection procedure (α = 0.01) and a Classification and Regression Tree (CART) analysis were performed to identify which prognostic factors were associated to OS in IR patients. From 2005 to 2017, 777 patients with ccRCC were treated with an anti-VEGF 1L therapy. Among 571 evaluable patients for IMDC score, 290 (51%) were classified as IR. With median follow-up 5.8 years (min: 0, max: 12.4) 212 deaths (73%) were observed and median OS was 25 months. Only platelet count was significantly associated to OS (hazard ratio 1.88 [95% CI 1.27-2.88] = 0.0017). Median OS for patients with PLT > UNL was 18 months [95% CI 12-23] versus 29 months [95% CI 21.4-35.7] for patients with normal PLT count. The selection of PLT count was confirmed on bootstrap samples and was also selected for the first split of the CART-tree analysis. Patients in the IR group have a heterogeneous prognosis. Elevated PLT count seems identifies a subgroup of patients with poor outcome in the IMDC intermediate-risk population with ccRCC.
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http://dx.doi.org/10.18632/oncotarget.27762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733622PMC
December 2020

Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Gustave Roussy, INSERM U1015, Villejuif, France.

Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
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http://dx.doi.org/10.1172/jci.insight.145207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934884PMC
January 2021

Physiologic colonic uptake of F-FDG on PET/CT is associated with clinical response and gut microbiome composition in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

Eur J Nucl Med Mol Imaging 2021 May 31;48(5):1550-1559. Epub 2020 Oct 31.

Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montréal, Québec, Canada.

Background: Immune checkpoint inhibitors (ICI) represent the backbone treatment for advanced non-small cell lung cancer (NSCLC). Emerging data suggest that increased gut microbiome diversity is associated with favorable response to ICI and that antibiotic-induced dysbiosis is associated with deleterious outcomes. F-FDG physiologic colonic uptake on PET/CT increases following treatment with antibiotics (ATB) and could act as a surrogate marker for microbiome composition and predict prognosis. The aim of this study was to determine if F-FDG physiologic colonic uptake prior to ICI initiation correlates with gut microbiome profiling and clinical outcomes in patients with advanced NSCLC.

Methods: Seventy-one patients with advanced NSCLC who underwent a PET/CT prior to ICI were identified. Blinded colonic contouring was performed for each colon segment and patients were stratified according to the median of the average colon SUV as well as for each segment in low vs. high SUV groups. Response rate, progression-free survival (PFS), and overall survival (OS) were compared in the low vs. high SUV groups. Gut microbiome composition was analyzed for 23 patients using metagenomics sequencing.

Results: The high colon SUV group had a higher proportion of non-responders (p = 0.033) and significantly shorter PFS (4.1 vs. 11.3 months, HR 1.94, 95% CI 1.11-3.41, p = 0.005). High caecum SUV correlated with numerically shorter OS (10.8 vs. 27.6 months, HR 1.85, 95% CI 0.97-3.53, p = 0.058). Metagenomics sequencing revealed distinctive microbiome populations in each group. Patients with low caecum SUV had higher microbiome diversity (p = 0.046) and were enriched with Bifidobacteriaceae, Lachnospiraceae, and Bacteroidaceae.

Conclusions: Lower colon physiologic F-FDG uptake on PET/CT prior to ICI initiation was associated with better clinical outcomes and higher gut microbiome diversity in patients with advanced NSCLC. Here, we propose that F-FDG physiologic colonic uptake on PET/CT could serve as a potential novel marker of gut microbiome composition and may predict clinical outcomes in this population.
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http://dx.doi.org/10.1007/s00259-020-05081-6DOI Listing
May 2021

Immune responses during COVID-19 infection.

Oncoimmunology 2020 08 25;9(1):1807836. Epub 2020 Aug 25.

Immunology, Gustave Roussy, Villejuif, France.

Over the past 16 years, three coronaviruses (CoVs), severe acute respiratory syndrome CoV (SARS-CoV) in 2002, Middle East respiratory syndrome CoV (MERS-CoV) in 2012 and 2015, and SARS-CoV-2 in 2020, have been causing severe and fatal human epidemics. The unpredictability of coronavirus disease-19 (COVID-19) poses a major burden on health care and economic systems across the world. This is caused by the paucity of in-depth knowledge of the risk factors for severe COVID-19, insufficient diagnostic tools for the detection of SARS-CoV-2, as well as the absence of specific and effective drug treatments. While protective humoral and cellular immune responses are usually mounted against these , immune responses to SARS-CoV2 sometimes derail towards inflammatory tissue damage, leading to rapid admissions to intensive care units. The lack of knowledge on mechanisms that tilt the balance between these two opposite outcomes poses major threats to many ongoing clinical trials dealing with immunostimulatory or immunoregulatory therapeutics. This review will discuss innate and cognate immune responses underlying protective or deleterious immune reactions against these pathogenic coronaviruses.
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http://dx.doi.org/10.1080/2162402X.2020.1807836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480812PMC
August 2020

Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors.

Oncoimmunology 2020 07 20;9(1):1794423. Epub 2020 Jul 20.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

Accumulating evidence from preclinical studies and human trials demonstrated the crucial role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade. In summary, it appears that a diverse intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota composition that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. In this review, we explore preclinical and translational studies highlighting how eubiotic and dysbiotic microbiota composition can affect progression-free survival in cancer patients.
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http://dx.doi.org/10.1080/2162402X.2020.1794423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466864PMC
July 2020

Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy.

Oncoimmunology 2020 06 3;9(1):1774298. Epub 2020 Jun 3.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
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http://dx.doi.org/10.1080/2162402X.2020.1774298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466862PMC
June 2020

Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses.

Oncoimmunology 2020 07 8;9(1):1789284. Epub 2020 Jul 8.

Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche DES Cordeliers, Paris, France.

Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.
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http://dx.doi.org/10.1080/2162402X.2020.1789284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458592PMC
July 2020

COVID-19: a challenge for oncology services.

Oncoimmunology 2020 05 5;9(1):1760686. Epub 2020 May 5.

Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.

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http://dx.doi.org/10.1080/2162402X.2020.1760686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458620PMC
May 2020

Antibiotics impair immunotherapy for urothelial cancer.

Nat Rev Urol 2020 Nov;17(11):605-606

Gustave Roussy Cancer Center, Villejuif, France.

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http://dx.doi.org/10.1038/s41585-020-0373-1DOI Listing
November 2020

The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Patients with Advanced Non-Small Cell Lung Cancer.

Cancer Immunol Res 2020 10 27;8(10):1243-1250. Epub 2020 Jul 27.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo City, Tokyo, Japan.

The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non-small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti-PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3-V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of UCG 13 and When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, UCG 13 and were enriched in patients with favorable ORR and PFS >6 months. UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI..
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0196DOI Listing
October 2020

Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage.

Science 2020 08;369(6506):936-942

Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Mice bearing harboring this prophage mounted a TMP-specific H-2K-restricted CD8 T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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http://dx.doi.org/10.1126/science.aax0701DOI Listing
August 2020

Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19.

Cell 2020 09 5;182(6):1401-1418.e18. Epub 2020 Aug 5.

INSERM U1287, Gustave Roussy Cancer Campus, Villejuif 94800, France; Département d'Hématologie, Gustave Roussy Cancer Campus, Villejuif 94800, France.

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14CD16 monocytes, accumulation of HLA-DR classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10CD101CXCR4 neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.
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http://dx.doi.org/10.1016/j.cell.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405878PMC
September 2020

Addition of Primary Metastatic Site on Bone, Brain, and Liver to IMDC Criteria in Patients With Metastatic Renal Cell Carcinoma: A Validation Study.

Clin Genitourin Cancer 2021 Feb 27;19(1):32-40. Epub 2020 Jun 27.

Department of Medical Oncology, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy.

Background: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria have been largely adopted in clinical practice. In a recent retrospective study, we assessed that the addition of the first site of metastatic disease to brain, bone, and liver improves prognostic stratification of patients with metastatic renal cell carcinoma (mRCC). Here, we performed an external validation in patients with mRCC. Our aim was to evaluate if the addition of a new independent variable could improve IMDC prognosis prediction and reduce heterogeneity within risk categories.

Patients And Methods: We selected all 1073 patients treated at a single institution for mRCC and included in the Institute Gustave Roussy Renal Cell Carcinoma database. All patients included received at least 1 line of targeted therapy or immune checkpoint inhibitors. Univariate and multivariate analyses (Cox regression model) were performed. Bootstrap validation of the final model was also carried out for internal validation. The IMDC modified classification was defined by the addition of the seventh variable, and we defined the modified IMDC good-risk criteria as 0 risks, intermediate-risk as 1 to 2 risks, and poor-risk as 3 or more risks.

Results: The presence of brain, bone, and/or liver as the first site of metastatic disease plus the other variables included in the IMDC score were statistically significant variables associated with overall survival (OS) after univariate and multivariate analysis and bootstrap validation. Finally, 122 (15%) patients had a modification of their initial risk category. The median OS in the poor-, intermediate-, and favorable-risk groups was 10, 26, and 52 months, respectively (P < .001). The bias-corrected concordance index in patients receiving immune checkpoint inhibitors (n = 241) was 0.71.

Conclusion: The addition of brain, bone, and/or liver metastases as an additional variable to the other IMDC variables improves the prognostic predictive power of the model.
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http://dx.doi.org/10.1016/j.clgc.2020.06.003DOI Listing
February 2021

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

Nat Med 2020 06 25;26(6):919-931. Epub 2020 May 25.

Service de Chirurgie Digestive et Oncologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1 T cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.
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http://dx.doi.org/10.1038/s41591-020-0882-8DOI Listing
June 2020

Incidence of patients with bone metastases at diagnosis of solid tumors in adults: a large population-based study.

Ann Transl Med 2020 Apr;8(7):482

Department of Orthopaedics, Zhejiang Provincial Key Laboratory of Orthopaedics, The Second Affiliated Hospital, and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.

Background: Bones are one of the most common metastatic sites for solid malignancies. Bone metastases can significantly increase mortality and decrease the quality of life of cancer patients. In the United States, around 350,000 people die each year from bone metastases. This study aimed to analyze and update the incidence and prognosis of bone metastases with solid tumors at the time of cancer diagnosis and its incidence rate for each solid cancer.

Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to find patients diagnosed with solid cancers originating from outside the bones and joints between 2010 and 2016. Data were stratified by age, sex, and race. Patients with a tumor or with an unknown bone metastases stage were excluded. We then selected most of the sites where cancer often occurred, leaving 2,207,796 patients for the final incidence analysis. For the survival analysis, patients were excluded if they were diagnosed at their autopsy or on their death certificate, or had unknown follow-ups. The incidence of bone metastases and overall survival was compared between patients with different primary tumor sites.

Results: We identified 2,470,634 patients, including 426,594 patients with metastatic disease and 113,317 patients with bone metastases, for incidence analysis. The incidence of bone metastases among the metastatic subset was 88.74% in prostate cancer, 53.71% in breast cancer, and 38.65% in renal cancer. In descending order of incidence, there were patients with other cancers in the genitourinary system (except for renal, bladder, prostate, and testicular cancer) (37.91%), adenocarcinoma of the lung (ADC) (36.86%), other gynecologic cancers (36.02%), small-cell lung cancer (SCLC) (34.56%), non-small cell lung cancer not otherwise specified and others [NSCLC (NOS/others)] (33.55%), and bladder (31.08%) cancers. The rate of bone metastases is 23.19% in SCLC, 22.50% in NSCLC (NOS/others), 20.28% in ADC, 8.44% in squamous cell carcinoma of the lung (SCC), and 4.11% in bronchioloalveolar carcinoma [NSCLC (BAC)]. As for the digestive system, the overall bone metastases rate was 7.99% in the esophagus, 4.47% in the gastric cancer, 4.42% in the hepatobiliary cancer, 3.80% in the pancreas, 3.26% in other digestive organs, 1.24% in the colorectum, and 1.00% in the anus. Overall, the incidence rate of bone metastases among the entire cohort in breast and prostate cancer was 3.73% and 5.69%, respectively.

Conclusions: The results of this study provide population-based estimates for the incidence rates of patients with bone metastases at initial diagnosis of their solid tumor. The findings can help clinicians to early detect bone metastases by bone screening to anticipate the occurrence of symptoms and favorably improve the prognosis.
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http://dx.doi.org/10.21037/atm.2020.03.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210217PMC
April 2020

New pathways in immune stimulation: targeting OX40.

ESMO Open 2020 02 9;5(1). Epub 2020 Feb 9.

INSERM U1015, Gustave Roussy Institute, Villejuif, France

Immune checkpoint blockers (ICB) reinvigorate the immune system by removing the molecular brakes responsible for the scarce activity of immune phenotypes against malignant cells. After having proven their remarkable role as monotherapy, combinations of anti-Programmed cell death 1 (PD-1)/Programmed death-ligand 1 (PD-L1) agents with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies, chemotherapy and/or anti-angiogenic compounds provide unprecedented results and durable responses across a variety of tumour types. Nevertheless, the main drawbacks of ICB are represented by primary and acquired resistance, translating into disease progression, as well as by immune-related toxicities. In this sense, novel strategies to foster the immune system through its direct stimulation are being tested in order to provide additional clinical improvements in patients with cancer. In this scenario, the co-stimulatory molecule OX40 (CD134) belongs to the next generation of immune therapeutic targets. Preliminary results of early clinical trials evaluating OX40 stimulation by means of different agents are encouraging. Here we review the rationale of OX40 targeting, highlighting the combination of OX40-directed therapies with different anticancer agents as a potential strategy to foster the immune system against malignant phenotypes.
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http://dx.doi.org/10.1136/esmoopen-2019-000573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046367PMC
February 2020

Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients.

Eur Urol 2020 08 4;78(2):195-206. Epub 2020 May 4.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medical Oncology, Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

Background: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC.

Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients.

Design, Setting, And Participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed.

Outcome Measurements And Statistical Analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients' therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors.

Results And Limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae).

Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers.

Patient Summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy.
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http://dx.doi.org/10.1016/j.eururo.2020.04.044DOI Listing
August 2020

Comedications influence immune infiltration and pathological response to neoadjuvant chemotherapy in breast cancer.

Oncoimmunology 2020 14;9(1):1677427. Epub 2019 Nov 14.

Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, U932, Immunity and Cancer, Institut Curie, PSL Research University, Paris, France.

Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2 BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in -positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC.
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http://dx.doi.org/10.1080/2162402X.2019.1677427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959439PMC
November 2019

On-target Toxicities Predictive of Survival in Metastatic Renal Cell Carcinoma (mRCC) Treated With Sunitinib: A Multicenter Retrospective Study.

Clin Genitourin Cancer 2020 04 5;18(2):e145-e156. Epub 2019 Dec 5.

Dipartimento di Medicina e Chirurgia, Università degli Studi dell'Insubria di Varese, Varese, Italy.

Background: Preliminary studies suggested that selected drug-related toxicities of sunitinib may correlate with a better prognosis.

Patients And Methods: From January 2006 through December 2015, we retrospectively analyzed data of 145 patients with metastatic renal cell carcinoma treated with sunitinib as a first-line therapy in 7 different Italian oncology departments. Hypertension, hypothyroidism, thrombocytopenia, neutropenia, and anemia were evaluated. Overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were compared in patients who developed and who did not develop a drug-related toxicity. A multivariate analysis using the Cox regression model was performed.

Results: We evaluated 145 patients (92 males; median age, 70 years); 105 (62.4%) patients experienced at least 1 toxicity: 66 (45.5%) patients developed hypothyroidism, 41 (28.3%) thrombocytopenia, 39 (26.9%) hypertension that required medical therapy, 22 (15.2%) anemia, and 11 (7.6%) neutropenia. The median PFS of patients who developed hypertension was 12 months (95% confidence interval [CI], 9-21 months) versus 9 months (95% CI, 7-12 months) in patients who did not develop toxicity; the median OS was 36 months (95% CI, 22 months to not reached) versus 26 months (95% CI, 18-34 months). For neutropenia, the median PFS was 17.5 months (95% CI, 9-65 months) versus 10 months (95% CI, 8-12 months); the median OS was 23 months (95% CI, 13 months to not reached) versus 28 months (95% CI, 22-35 months). At univariate and multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression (hazard ratio, 0.47; 95% CI, 0.28-0.78 and hazard ratio, 0.26; 95% CI, 0.09-0.76, respectively).

Conclusions: Many patients developed toxicities during treatment with sunitinib; hypertension and neutropenia were related to longer PFS in our cohort.
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http://dx.doi.org/10.1016/j.clgc.2019.10.003DOI Listing
April 2020

Renal Cell Carcinoma with bone metastases isn't always bad.

Oncotarget 2019 Jul 16;10(44):4511-4512. Epub 2019 Jul 16.

Department of Cancer Medicine, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.

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http://dx.doi.org/10.18632/oncotarget.27076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642045PMC
July 2019

A new prognostic model for survival in second line for metastatic renal cell carcinoma: development and external validation.

Angiogenesis 2019 08 9;22(3):383-395. Epub 2019 Feb 9.

Departments of Medical Oncology, Gustave Roussy, 114 Rue Edward Vaillant, 94800, Villejuif, France.

Background: In patients with metastatic renal cell carcinoma (mRCC), the oncologic benefit of second-line treatment for high volume tumors or presence of more than five risk factors remain to be defined. Our aim was to develop and externally validate a new model most likely to correctly predict overall survival (OS) categories in second line.

Method: mRCC patients treated within clinical trials at Gustave Roussy Cancer Campus (GRCC) formed the discovery set. Patients from two phase III trials from Pfizer database (PFIZERDB), AXIS (NCT00678392), and INTORSECT (NCT00474786), formed the external validation set. New prognostic factors were analyzed using a multivariable Cox model with a backward selection procedure. Performance of the GRCC model and the prognostic classification scheme derived from it, measuring by R, c-index, and calibration, was evaluated on the validation set and compared to MSKCC and IMDC models.

Results: Two hundred and twenty-one patients were included in the GRCC cohort and 855 patients in the PFIZERDB. Median OS was similar in the discovery and validation cohorts (16.8 [95% CI 12.9-21.7] and 15.3 [13.6-17.2] months, respectively). Backward selection procedure identified time from first to second-line treatment and tumor burden as new independent prognostic factors significantly associated to OS after adjusting for IMDC prognostic factors (HR 1.68 [1.23-2.31] and 1.43 [1.03-1.99], respectively). Dividing patients into four risk groups, based on the number of factors selected in GRCC model, median OS from the start of second line in the validation cohort was not reached (NE) [95% CI 24.9-NE] in the favorable risk group (n = 20), 21.8 months [18.6-28.2] in the intermediate-risk group (n = 367), 12.7 months [11.0-15.8] in the low poor-risk group (n = 347), and 5.5 months [4.7-6.4] in the high poor-risk group (n = 121). Finally, this model and its prognostic classification scheme provided the better fit, with higher R and higher c-index compared to other possible classification schemes.

Conclusion: A new prognostic model was developed and validated to estimate overall survival of patients with previously treated mRCC. This model is an easy-to-use tool that allows accurate estimation of patient survival to inform decision making and follow-up after first line for mRCC.
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http://dx.doi.org/10.1007/s10456-019-09664-2DOI Listing
August 2019

Les métastases cérébrales de cancer du rein, un défi clinique.

Bull Cancer 2018 Dec;105 Suppl 3:S261-S267

Département de médecine oncologique, Gustave-Roussy, Villejuif, France. Electronic address:

Brain Metastases In Renal Cell Carcinoma, An Unmet Need: Brain metastases from renal cell carcinomas are associated with dismal prognosis and might be present in up to 10 % of metastatic patients. Biologically, the blood brain barrier might be disrupted in brain metastases and thus do not exclusively account for treatment resistance. Brain metastases often acquire additional molecular alterations that might provide aggressive features. They are also associated with high lymphocytic infiltration and expression of immune checkpoints PD-1/PD-L1. In clinical routine, scores based on metastatic volume and patients' performance status might help better predict survival. The cornerstone of brain metastases treatment is stereotactic radiation therapy if patients are eligible, while systemic treatments such as antiangiogenics and immune checkpoint inhibitors only provide limited disease control. Early identification of patients with brain metastases from renal cell carcinomas and promotion of dedicated clinical trials will be important to try and improve current clinical management.
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http://dx.doi.org/10.1016/S0007-4551(18)30381-3DOI Listing
December 2018

The intimate relationship between gut microbiota and cancer immunotherapy.

Gut Microbes 2019 19;10(3):424-428. Epub 2018 Oct 19.

a Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) , Montréal , Qc , Canada.

Immunotherapy is widely used to treat a large variety of malignancies and has revolutionized the therapeutic approach to cancer. Major efforts are ongoing to identify biomarkers that predict response to immunotherapy as well as new strategies to improve ICI efficacy and clinical outcomes. Studies have shown that the gut microbiome determines the extent to which ICIs may invigorate the anticancer immune response. Here, the authors review recent studies that have described the effects of the gut microbiota on the efficacy of CTLA-4 and PD-1 inhibitors and outline potential future clinical directions of these findings.
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http://dx.doi.org/10.1080/19490976.2018.1527167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546322PMC
December 2019

[In bacteria veritas: pronostic role of intestinal microbiote in cancer therapy].

Med Sci (Paris) 2018 Aug-Sep;34(8-9):657-659. Epub 2018 Sep 19.

Centre de recherche du centre hospitalier de l'université de Montréal (CRCHUM), 900 rue Saint-Denis, H2X 3H8 Montréal, Québec, Canada - Division d'hémato-oncologie, département de médicine, centre hospitalier de l'université de Montréal (CHUM), Montréal, Québec, Canada.

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http://dx.doi.org/10.1051/medsci/20183408009DOI Listing
April 2019