The CRCT presents its Top 5 publications from its teams in 2022. Find all the 2022 publications of each team on their dedicated page.
Ultrarapid Lytic Granule Release from CTLs Activates Ca2+-Dependent Synaptic Resistance Pathways in Melanoma Cells
Filali, Liza, Marie-Pierre Puissegur, Kevin Cortacero, Sylvain Cussat-Blanc, Roxana Khazen, Nathalie, Van Acker, François-Xavier Frenois, et al. « Ultrarapid Lytic Granule Release from CTLs Activates Ca2+-Dependent Synaptic Resistance Pathways in Melanoma Cells ». Science Advances 2022 Feb 18;8(7):eabk3234. doi: 10.1126/sciadv.abk3234. Epub 2022 Feb 16.
Abstract
Human cytotoxic T lymphocytes (CTLs) exhibit ultrarapid lytic granule secretion, but whether melanoma cells mobilize defense mechanisms with commensurate rapidity remains unknown. We used single-cell time-lapse microscopy to offer high spatiotemporal resolution analyses of subcellular events in melanoma cells upon CTL attack. Target cell perforation initiated an intracellular Ca2+ wave that propagated outward from the synapse within milliseconds and triggered lysosomal mobilization to the synapse, facilitating membrane repair and conferring resistance to CTL induced cytotoxicity. Inhibition of Ca2+ flux and silencing of synaptotagmin VII limited synaptic lysosomal exposure and enhanced cytotoxicity. Multiplexed immunohistochemistry of patient melanoma nodules combined with automated image analysis showed that melanoma cells facing CD8+ CTLs in the tumor periphery or peritumoral area exhibited significant lysosomal enrichment. Our results identified synaptic Ca2+ entry as the definitive trigger for lysosomal deployment to the synapse upon CTL attack and highlighted an unpredicted defensive topology of lysosome distribution in melanoma nodules.
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Contact : Team DynAct, Molecular dynamics of Lymphocyte Interactions, directed by Salvatore Valitutti
Targeting the Liver X Receptor with Dendrogenin A Differentiates Tumour Cells to Secrete Immunogenic Exosome-Enriched Vesicles
Record, Michel, Mehdi Attia, Kevin Carayon, Laly Pucheu, Julio Bunay, Régis Soulès, Silia Ayadi, et al. « Targeting the Liver X Receptor with Dendrogenin A Differentiates Tumour Cells to Secrete Immunogenic Exosome-Enriched Vesicles ». Journal of Extracellular Vesicles 2022 Apr;11(4):e12211. doi: 10.1002/jev2.12211.
Abstract
Tumour cells are characterized by having lost their differentiation state. They constitutively secrete small extracellular vesicles (sEV) called exosomes when they come from late endosomes. Dendrogenin A (DDA) is an endogenous tumour suppressor cholesterol-derived metabolite. It is a new class of ligand of the nuclear Liver X receptors (LXR) which regulate cholesterol homeostasis and immunity. We hypothesized that DDA, which induces tumour cell differentiation, inhibition of tumour growth and immune cell infiltration into tumours, could functionally modify sEV secreted by tumour cells. Here, we have shown that DDA differentiates tumour cells by acting on the LXRβ. This results in an increased production of sEV (DDA-sEV) which includes exosomes. The DDA-sEV secreted from DDA-treated cells were characterized for their content and activity in comparison to sEV secreted from control cells (C-sEV). DDA-sEV were enriched, relatively to C-sEV, in several proteins and lipids such as differentiation antigens, “eat-me” signals, lipidated LC3 and the endosomal phospholipid bis(monoacylglycero)phosphate, which stimulates dendritic cell maturation and a Th1 T lymphocyte polarization. Moreover, DDA-sEV inhibited the growth of tumours implanted into immunocompetent mice compared to control conditions. This study reveals a pharmacological control through a nuclear receptor of exosome-enriched tumour sEV secretion, composition and immune function. Targeting the LXR may be a novel way to reprogram tumour cells and sEV to stimulate immunity against cancer.
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Contact : Team INOV, Cholesterol Metabolism and Therapeutic Innovations, directed by Marc Poirot and Sandrine Silvente Poirot
SAR442085, a Novel Anti-CD38 Antibody with Enhanced Antitumor Activity against Multiple Myeloma
Kassem, Sahar, Béré K. Diallo, Nizar El-Murr, Nadège Carrié, Alexandre Tang, Alain Fournier, Hélène Bonnevaux, et al. « SAR442085, a Novel Anti-CD38 Antibody with Enhanced Antitumor Activity against Multiple Myeloma ». Blood 139, 2022 Feb 24;139(8):1160-1176. doi: 10.1182/blood.2021012448.
Abstract
Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients’ primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients’ primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.
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Link to the article (publisher’s website)
Contact : Team GENIM, Genomic and Immunology of myeloma, directed by Ludovic Martinet and Hervé Avet-Loiseau
4. In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present From Diagnosis in Tiny, Undetectable Subclonal Populations
Lannes R, Samur M, Perrot A, Mazzotti C, Divoux M, Cazaubiel T, Leleu X, Schavgoulidze A, Chretien ML, Manier S, Adiko D, Orsini-Piocelle F, Lifermann F, Brechignac S, Gastaud L, Bouscary D, Macro M, Cleynen A, Mohty M, Munshi N, Corre J, Avet-Loiseau H. In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present From Diagnosis in Tiny, Undetectable Subclonal Populations. J Clin Oncol.2022 Nov 7;JCO2101987. doi: 10.1200/JCO.21.01987
Abstract
Purpose: Multiple myeloma (MM) is characterized by copy number abnormalities (CNAs), some of which influence patient outcomes and are sometimes observed only at relapse(s), suggesting their acquisition during tumor evolution. However, the presence of micro-subclones may be missed in bulk analyses. Here, we use single-cell genomics to determine how often these high-risk events are missed at diagnosis and selected at relapse.
Materials and methods: We analyzed 81 patients with plasma cell dyscrasias using single-cell CNA sequencing. Sixty-six patients were selected at diagnosis, nine at first relapse, and six in presymptomatic stages. A total of 956 newly diagnosed patients with MM and patients with first relapse MM have been identified retrospectively with required cytogenetic data to evaluate enrichment of CNA risk events and survival impact.
Results: A total of 52,176 MM cells were analyzed. Seventy-four patients (91%) had 2-16 subclones. Among these patients, 28.7% had a subclone with high-risk features (del(17p), del(1p32), and 1q gain) at diagnosis. In a patient with a subclonal 1q gain at diagnosis, we analyzed the diagnosis, postinduction, and first relapse samples, which showed a rise of the high-risk 1q gain subclone (16%, 70%, and 92%, respectively). In our clinical database, we found that the 1q gain frequency increased from 30.2% at diagnosis to 43.6% at relapse (odds ratio, 1.78; 95% CI, 1.58 to 2.00). We subsequently performed survival analyses, which showed that the progression-free and overall survival curves were superimposable between patients who had the 1q gain from diagnosis and those who seemingly acquired it at relapse. This strongly suggests that many patients had 1q gains at diagnosis in microclones that were missed by bulk analyses.
Conclusion: These data suggest that identifying these scarce aggressive cells may necessitate more aggressive treatment as early as diagnosis to prevent them from becoming the dominant clone.
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Contact : Team GENIM, Genomic and Immunology of myeloma, directed by Ludovic Martinet and Hervé Avet-Loiseau
Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non-Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial
Julien Mazieres, Claire Lafitte, Charles Ricordel, Laurent Greillier, Elodie Negre, Gérard Zalcman, Charlotte Domblides, Jeannick Madelaine, Jaafar Bennouna, Céline Mascaux, Denis Moro-Sibilot, François Pinquie, Alexis B Cortot, Josiane Otto, Jacques Cadranel, Alexandra Langlais, Franck Morin, Virginie Westeel, Benjamin Besse
Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non-Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial
J Clin Oncol. 2022 Mar 1;40(7):719-728.doi: 10.1200/JCO.21.01455. Epub 2022 Jan 24.
Clinical publication in connection with the IUCTo
Abstract
Purpose: HER2 exon 20 insertions and point mutations are oncogenic drivers found in 1%-2% of patients with non-small-cell lung cancer (NSCLC). No targeted therapy is approved for this subset of patients. We prospectively evaluated the effectiveness of the combination of two antibodies against human epidermal growth factor 2 (HER2 [HER2] trastuzumab and pertuzumab with docetaxel; trastuzumab and pertuzumab) and docetaxel.
Methods: The IFCT 1703-R2D2 trial is a multicenter, nonrandomized phase II study. Patients with HER2-mutated, advanced NSCLC who progressed after ≥ 1 platinum-based treatment were enrolled. Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m2 every 3 weeks. The primary outcome was the objective response rate (ORR). Other end points included the duration of response, progression-free survival, and safety (NCT03845270).
Results: Forty-five patients were enrolled and treated. The median age was 64.5 years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an Eastern Cooperative Oncology Group performance status of 2, and 30% had brain metastases. The objective response rate was 29% (n = 13), and 58% had stable disease (n = 26). The median progression-free survival was 6.8 months (95% CI, 4.0 to 8.5). The median duration of response in patients with a confirmed response (n = 13) was 11 months (95% CI, 2.9 to 14.9). Grade 3/4 treatment-related adverse events were observed in 64% of the patients. No patient discontinued treatment because of toxicity. The most frequent grade ≥ 3 treatment-related adverse events were neutropenia (33%), diarrhea (13%), and anemia (9%).
Conclusion: Triple therapy with trastuzumab, pertuzumab, and docetaxel is feasible and effective for HER2-mutated pretreated advanced NSCLC. These results highlight the effectiveness of the HER2 antibody-based strategy, which should be considered for these patients.
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Contact : Team SIGNATHER, Cell Signalling, Oncogenesis and Therapeutics, directed by Gilles Favre and Olivier Sordet
Toulouse Cancer Research Center (Oncopole)
Toulouse - FR
CRCT-Oncopole Follow 1,433 1,279
Compte officiel du Centre de Recherches en Cancérologie de Toulouse
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🇬🇧Cytidine deaminase-dependent mitochondrial biogenesis as a potential vulnerability in pancreatic cancer cells. ImPact team @CordelierPierre article from @crctoncopole published in @CommsBio
➡️https://www.crct-inserm.fr/en/targeting-the-energy-production-process-in-pancreatic-cancer-cells-which-relies-on-an-enzyme-called-cytidine-deaminase-could-make-these-cells-more-vulnerable/
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