SN 2022oqm: A Multi-peaked Calcium-rich Transient from a White Dwarf Binary Progenitor System

We present the photometric and spectroscopic evolution of SN 2022oqm, a nearby multi-peaked hydrogen- and helium-weak calcium-rich transient (CaRT). SN 2022oqm was detected 19.9 kpc from its host galaxy, the face-on spiral galaxy NGC 5875. Extensive spectroscopic coverage reveals a hot (T >= 40,000 K) continuum and carbon features observed ~1 day after discovery, SN Ic-like photospheric-phase spectra, and strong forbidden calcium emission starting 38 days after discovery. SN 2022oqm has a relatively high peak luminosity (MB = -17 mag) for CaRTs, making it an outlier in the population. We determine that three power sources are necessary to explain SN 2022oqm's light curve, with each power source corresponding to a distinct peak in its light curve. The first peak of the light curve is powered by an expanding blackbody with a power law luminosity, consistent with shock cooling by circumstellar material. Subsequent peaks are powered by a double radioactive decay model, consistent with two separate sources of photons diffusing through an optically thick ejecta. From the optical light curve, we derive an ejecta mass and 56Ni mass of ~0.89 solar masses and ~0.09 solar masses, respectively. Detailed spectroscopic modeling reveals ejecta that is dominated by intermediate-mass elements, with signs that Fe-peak elements have been well-mixed. We discuss several physical origins for SN 2022oqm and favor a white dwarf progenitor model. The inferred ejecta mass points to a surprisingly massive white dwarf, challenging models of CaRT progenitors.Comment: 33 pages, 17 figures, 5 tables, Submitted to Ap

Immune microenvironment of ovarian cancer : evolution under chemo/immunotherapy and characterization of the heterogeneity and role of antibody-secreting cells

Mon projet concerne les carcinomes ovariens séreux de haut grade (HGSOC) et avait pour objectifs i) d'étudier l'impact de la chimiothérapie (CT) +/- immunothérapie (IT) sur les cellules immunitaires adaptatives, ii) d’identifier des biomarqueurs de réponse à ces traitements, et iii) de caractériser l'hétérogénéité phénotypique et fonctionnelle des cellules sécrétant des anticorps (ASC) infiltrant la tumeur et leur impact clinique. A partir d'échantillons de l'essai clinique de phase II NeoPembrOv (PI : Pr Ray-Coquard I.), qui vise à évaluer l'efficacité du Pembrolizumab en association avec la CT dans les HGSOC non résécables d’emblée, et par du RNA-seq et des marquages de tumeurs par immunofluorescence multiplexée (multi-IF), nous montrons que la chimiothérapie augmente de manière significative la densité des structures lymphoïdes tertiaires, des lymphocytes CD8 et des ASC IgA+ à la fois dans la tumeur et le stroma, et des macrophages de type 2, tandis que les lymphocytes B totaux et les ASC IgG+ restent stables. L’addition d’anti-PD-1 est associée à une augmentation significative des lymphocytes T CD8+PD1+ intra-épithéliaux. Une infiltration monocytaire exprimant de faibles niveaux de TREM2 ainsi qu’une infiltration intra-épithéliale de CD8+PD1+ sous traitement sont associées à la réponse au traitement évaluée par une absence de rechute à 24 mois. Au contraire, une forte densité en cellules endothéliales exprimant des taux élevés de PGF avant traitement était associée à une résistance à la combinaison CT+anti-PD-1. Grâce à des analyses par cytométrie de flux multiparamétrique, des marquages multi-IF associés à la pathologie digitale et du séquençage d’ARN en cellules uniques, nous montrons que les HGSOC sont infiltrés par des cellules B aux différents stades de différenciation, dont 40 % sont des ASC constitués à la fois de plasmablastes et de cellules plus matures spécialisées dans le sécrétion d’anticorps . Ces ASC se localisent dans le stroma et dans une moindre mesure dans la tumeurs, produisent majoritairement des IgG, mais une fraction des patientes est enrichie en ASC IgA+. La chimiothérapie néo-adjuvante (NACT) induit un remodelage du compartiment B avec une augmentation des lymphocytes B naïfs et des ASC et des B mémoires exprimant IgA. L'exploration des données transcriptomiques (RNA-seq) du TCGA et l'analyse multi-IF d’une cohorte de patientes a révélé qu'une densité tumorale élevée d'ASC à IgG, et dans une moindre mesure d’ASC à IgA, est associée à une meilleure survie dans les HGSOC. De plus, un ratio IgA/IgG élevé est associé à une moins bonne survie sans progression, suggérant un impact délétère des IgA. En revanche, aucun impact n’est retrouvé pour les patientes traitées par NACT. L’analyse des réactivités antigéniques des anticorps dans le sérum et les tumeurs (n = 35) à l’aide de puces à peptides chevauchant montre que les IgG et les IgA ciblent principalement des protéines différentes et que les antigènes associés à la tumeur et les cancer-testis antigènes sont plus fréquemment ciblées dans le micro-environnement tumoral par les IgG que par les IgA. Enfin, nos données préliminaires de scRNA-seq combiné au BCR-seq montrent une plus faible expansion clonale dans les tumeurs traitées versus naïves, à la fois dans les lymphocytes B mémoires et les ASC, et que les ASC à IgA présentent un phénotype immunosuppresseur avec une régulation à la hausse de gènes impliqués dans l'angiogenèse (VEGFA, VEGFB, PIGF, ANG, AGGF1).My project concerns high-grade serous ovarian carcinomas (HGSOC) and has the objectives i) to study the impact of chemotherapy (CT) +/- immunotherapy (IT) on adaptive immune cells, ii) to identify biomarkers of response to these treatments, and iii) to characterize the phenotypic and functional heterogeneity of antibody-secreting cells (ASC) infiltrating the tumor and their clinical impact. Using samples from the NeoPembrOv phase II clinical trial (PI: Pr Ray-Coquard I.), which aims to assess the efficacy of Pembrolizumab in combination with CT in unresectable HGSOC, and by analysing RNA-seq and multiplexed immunofluorescence (multi-IF) tumor staining data, we show that chemotherapy significantly increases the density of tertiary lymphoid structures, CD8 lymphocytes and IgA+ ASCs in both the tumor and the stroma, and type 2 macrophages, while total B cells and IgG+ ASCs remain stable. The addition of anti-PD-1 is associated with a significant increase in intraepithelial CD8+PD1+ T cells. Monocytic infiltration expressing low levels of TREM2 as well as intraepithelial infiltration of CD8+PD1+ under treatment are associated with response defined as an absence of relapse at 24 months. On the contrary, a high density of endothelial cells expressing high levels of PGF before treatment was associated with resistance to the CT+anti-PD-1 combination. Using multiparameter flow cytometry analyses, multi-IF labeling associated with digital pathology and single-cell RNA sequencing, we show that HGSOCs are infiltrated by B cells at different stages of differentiation, of which 40% are ASCs consisting of both plasmablasts and more mature cells specialized in antibody secretion. These ASCs are localized in the stroma and to a lesser extent in the tumors, produce mainly IgG, but a fraction of the patients is enriched in ASC IgA+. Neoadjuvant chemotherapy (NACT) induces a remodeling of the B compartment with an increase in naïve B lymphocytes and ASCs and memory B cells expressing IgA. TCGA transcriptomic (RNA-seq) data mining and multi-IF analysis of a cohort of patients revealed that a high tumor density of IgG ASC, and to a lesser extent of IgA ASC , is associated with better survival in HGSOC. In addition, a high IgA/IgG ratio is associated with poorer progression-free survival, suggesting a deleterious impact of IgA. On the other hand, no impact was found for patients treated with NACT. Analysis of antibody antigen reactivities in serum and tumors (n=35) using overlapping peptide arrays shows that IgG and IgA mainly target different proteins and that tumor-associated antigens and cancer-testis antigens are more frequently targeted in the tumor microenvironment by IgG than by IgA. Finally, our preliminary data of scRNA-seq combined with BCR-seq show a lower clonal expansion in treated versus naïve tumors, both in memory B cells and ASCs, and that IgA ASCs exhibit an immunosuppressive phenotype with upregulation of genes involved in angiogenesis (VEGFA, VEGFB, PIGF, ANG, AGGF1)

Is There an Age Threshold for Holding Off on Testing Novel Therapies?

International audiencePurpose of Review We will review the reasons that explain the poor accrual of elderly patients to clinical trials, then we will discuss the relevance of an age threshold for holding off on testing novel therapies. Recent Findings Little progress has been made in enrolling elderly patients in clinical trials. Summary Reasons to hold off on testing novel therapies in elderly patients are mainly explained by exclusion criteria and industrials' reluctance to include elderly patients for fear of negative results. No age threshold should exist for testing novel therapies as long as well-designed clinical trials are developed and requested by regulatory authorities. Furthermore, clinical trials assessing novel anticancer therapies such as targeted therapies or immune checkpoint inhibitors should be developed in elderly patients regardless of age as these therapies may present a favorable benefit-risk profile compared to chemotherapy which is often more toxic and at risk of geriatric deconditioning

Toxicity of Cancer Therapies in Older Patients

International audienceIn clinical practice, older patients are often undertreated due to underrepresentation in clinical trials and fear of toxicity. Our objective was therefore to review toxicities that are specific to older cancer patients, to review risk factors in order to help physicians guide their decisions, and to review interventions that can be implemented in routine clinical practice to prevent toxicity induced by cancer therapies. On the whole, reviews report similar number and frequency as well as similar grade 3 or 4 adverse events between subjects older and younger than 65 years. Yet patients included in clinical trials are often not representative of real-life patients and are often fit older cancer patients. Moreover, tolerance to the additive impact of multiple adverse effects is different between older and younger patients. And specific symptoms such as stomatitis may cause a series of consequences such as dehydration, denutrition, renal insufficiency, and adverse events of renally excreted drugs. Older patients are at high risk of toxicity due to many factors but mainly due to the prevalence of frailty in this population that has been estimated to be around 40% increasing the risk of chemotherapy intolerance. As a consequence, interventions must be implemented according to altered domains of comprehensive geriatric assessment in order to improve anticancer tolerance. These interventions are reviewed here

BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges

BRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate–ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of BRCA1/2-mutated tumors, especially of BRCA1/2 high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept. However, PARPi efficiency differs among patients, and most of them will develop resistance, particularly in the relapse setting. In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations. Of note, as several mechanisms of primary or secondary resistance to PARPi have been described, BRCA1/2 reversion mutations that restore HR pathways are by far the most reported. First, the type and location of the BRCA1/2 primary mutation have been associated with PARPi and platinum-salt sensitivity and impact the probability of the occurrence and the type of secondary reversion mutation. Furthermore, the presence of multiple reversion mutations and the variation of allelic frequency under treatment underline the role of intratumor heterogeneity (ITH) in treatment resistance. Of note, circulating tumor DNA might help us to detect and characterize reversion mutations and ITH to finally refine the treatment strategy. Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients

Neoadjuvant immune checkpoint inhibitors in cancer, current state of the art

International audienceImmunotherapy has been a revolution in cancer management in the metastatic setting. This has led to a prompt evaluation of such therapies in earlier stages. This article discusses the still limited amount of data finding the rationale to assess such therapy in this setting and reviews preclinical and clinical data available. Overall, neoadjuvant immunotherapy is a promising approach for the treatment of cancers and the rationale supporting its use is strong. Neoadjuvant immunotherapy resulted, in the majority of clinical trials, in improved pathologic complete response rates with a favorable toxicity profile and no delay in surgery. Various regimens were effective: inhibitory immune check-point blockers (IICPB) alone, combination of PD-1 and CTLA-4 inhibitors, combination of chemotherapy (CT) and IICPB, phased CT and IICPB (either IICPB before CT or IICPB after CT). Yet the question whether neoadjuvant immunotherapy will benefit to patients in terms of disease-free and, ultimately, overall survival remains unknown

Rapalog-mediated repression of Tribbles pseudokinase 3 regulates pre-mRNA splicing

International audienceRapalogs have become standard-of-care in patients with metastatic breast, kidney, and neuroendocrine cancers. Nevertheless, tumor escape occurs after several months in most patients, highlighting the need to understand mechanisms of resistance. Using a panel of cancer cell lines, we show that rapalogs downregulate the putative protein kinase TRIB3 (tribbles pseudokinase 3). Blood samples of a small cohort of patients with cancer treated with rapalogs confirmed downregulation of TRIB3. Downregulation of TRIB3 was mediated by LRRFIP1 independently of mTOR and disrupted its interaction with the spliceosome, where it participated in rapalog-induced deregulation of RNA splicing. Conversely, overexpression of TRIB3 in a panel of cancer cell lines abolished the cytotoxic effects of rapalogs. These findings identify TRIB3 as a key component of the spliceosome, whose repression contributes significantly to the mechanism of resistance to rapalog therapy. SIGNIFICANCE: Independent of mTOR signaling, rapalogs induce cytoxicity by dysregulating spliceosome function via repression of TRIB3, the loss of which may, in the long term, contribute to therapeutic resistance