Highlights d IPH5201 and IPH5301 block cell-borne and soluble CD39 and CD73, respectively d IPH5201 maintains immunogenic extracellular ATP d When used in combination with chemotherapy, IPH5201 promotes antitumor immunity d Targeting CD39 and CD73 synergistically promotes cancer patient T cell activation

Variation in the lengths of restriction fragments (RFLPs) of the whole chloroplast DNA molecule was studied in 174 populations of Quercus ilex L. sampled over the entire distribution of this evergreen and mainly Mediterranean oak species. By using five endonucleases, 323 distinct fragments were obtained. From the 29 and 17 cpDNA changes identified as site and length mutations, respectively, 25 distinct chlorotypes were distinguished, mapped and treated cladistically with a parsimony analysis, using as an outgroup Q. alnifolia Poech, a closely related evergreen oak species endemic to Cyprus where Q. ilex does not grow. The predominant role of Q. ilex as maternal parent in hybridization with other species was reflected by the occurrence of a single very specific lineage of related chlorotypes, the most ancestral and recent ones being located in the southeastern and in the northwestern parts of the species' geographical distribution, respectively. The lineage was constituted of two clusters of chlorotypes observed in the 'ilex' morphotyped populations of the Balkan and Italian Peninsulas (including the contiguous French Riviera), respectively. A third cluster was divided into two subclusters identified in the 'rotundifolia' morphotyped populations of North Africa, and of Iberia and the adjacent French regions, respectively. Postglacial colonization probably started from three distinct southerly refugia located in each of the three European peninsulas, and a contact area between the Italian and the Iberian migration routes was identified in the Rhône valley (France). Chlorotypes identical or related to those of the Iberian cluster were identified in the populations from Catalonia and the French Languedoc region, which showed intermediate morphotypes, and in the French Atlantic populations which possessed the 'ilex' morphotype, suggesting the occurrence of adaptive morphological changes in the northern part of the species' distribution.

The results support a Middle-Eastern or a central Mediterranean origin for cork oak with subsequent westward colonization during the Tertiary Period, and suggest that the 'ilex' chlorotype variation does not reflect entirely cytoplasmic introgression by Q. ilex but originated partly in Q. suber.

Antiviral monoclonal antibodies (mAbs) represent promising therapeutics. However, most mAbs-based immunotherapies conducted so far have only considered the blunting of viral propagation and not other possible therapeutic effects independent of virus neutralization, namely the modulation of the endogenous immune response. As induction of long-term antiviral immunity still remains a paramount challenge for treating chronic infections, we have asked here whether neutralizing mAbs can, in addition to blunting viral propagation, exert immunomodulatory effects with protective outcomes. Supporting this idea, we report here that mice infected with the FrCasE murine retrovirus on day 8 after birth die of leukemia within 4–5 months and mount a non-protective immune response, whereas those rapidly subjected to short immunotherapy with a neutralizing mAb survive healthy and mount a long-lasting protective antiviral immunity with strong humoral and cellular immune responses. Interestingly, the administered mAb mediates lysis of infected cells through an antibody-dependent cell cytotoxicity (ADCC) mechanism. In addition, it forms immune complexes (ICs) with infected cells that enhance antiviral CTL responses through FcγR-mediated binding to dendritic cells (DCs). Importantly, the endogenous antiviral antibodies generated in mAb-treated mice also display the same properties, allowing containment of viral propagation and enhancement of memory cellular responses after disappearance of the administered mAb. Thus, our data demonstrate that neutralizing antiviral mAbs can act as immunomodulatory agents capable of stimulating a protective immunity lasting long after the end of the treatment. They also show an important role of infected-cells/antibody complexes in the induction and the maintenance of protective immunity through enhancement of both primary and memory antiviral T-cell responses. They also indicate that targeting infected cells, and not just viruses, by antibodies can be crucial for elicitation of efficient, long-lasting antiviral T-cell responses. This must be considered when designing antiviral mAb-based immunotherapies.

As a result of the early domestication and extensive cultivation of the olive tree throughout the Mediterranean Basin, the wild-looking forms of olive (oleasters) presently observed constitute a complex, potentially ranging from wild to feral forms. Allozyme variation was analysed at 10 loci in 31 large and 44 small oleaster populations distributed in various habitats of the Mediterranean Basin and in two populations of the wild subspecies Olea europaea subsp (ssp) guanchica, endemic to the Canary islands and closely related to oleasters. At eight polymorphic loci, 25 alleles were identified. Genetic evidence that nondomesticated oleasters still survive locally was provided by the occurrence of four and one alleles shared exclusively by the eight western and two eastern oleaster populations, respectively, which were collected in forests potentially containing genuinely wild forms according to environmental, historical and demographic criteria. As reported previously from cytoplasmic and RAPDs analysis, substantial genetic differentiation was observed between the eastern oleaster populations genetically close to most olive clones cultivated in the Mediterranean Basin, and the western populations that are related to the wild Canarian populations. In addition, the occurrence of significantly lower heterozygosity in cultivated olive than in oleasters, whatever their origin, suggests that intensive selection involving inbreeding has taken place under cultivation to obtain particular characteristics in the olive cultivars.

The tumor immune microenvironment contributes to tumor initiation, progression, and response to therapy. Among the immune cell subsets that play a role in the tumor microenvironment, innate-like T cells that express T cell receptors composed of γ and δ chains (γδ T cells) are of particular interest. γδ T cells can contribute to the immune response against many tumor types (lymphoma, myeloma, melanoma, breast, colon, lung, ovary, and prostate cancer) directly through their cytotoxic activity and indirectly by stimulating or regulating the biological functions of other cell types required for the initiation and establishment of the anti-tumor immune response, such as dendritic cells and cytotoxic CD8+ T cells. However, the notion that tumor-infiltrating γδ T cells are a good prognostic marker in cancer was recently challenged by studies showing that the presence of these cells in the tumor microenvironment was associated with poor prognosis in both breast and colon cancer. These findings suggest that γδ T cells may also display pro-tumor activities. Indeed, breast tumor-infiltrating γδ T cells could exert an immunosuppressive activity by negatively regulating dendritic cell maturation. Furthermore, recent studies demonstrated that signals from the microenvironment, particularly cytokines, can confer some plasticity to γδ T cells and promote their differentiation into γδ T cells with regulatory functions. This review focuses on the current knowledge on the functional plasticity of γδ T cells and its effect on their anti-tumor activities. It also discusses the putative mechanisms underlying γδ T cell expansion, differentiation, and recruitment in the tumor microenvironment.

Summary — In this paper we review the characteristics of the floral biology, life cycle and breeding system in the genus Quercus. The species of this genus are self-incompatible and have very long life spans. The focus of our review is on the effects of gene flow on the structuration of genetic variation in these species. We have examined the influence of gene flow in 2 ways: 1) by measuring the physical dispersal of pollen, seed and vegetative organs; and 2) by using nuclear and cytoplasmic markers to estimate genetic parameters (F is , N m

BackgroundTriple-negative breast cancer (TNBC) treatment is currently restricted to chemotherapy. Hence, tumor-specific molecular targets and/or alternative therapeutic strategies for TNBC are urgently needed. Immunotherapy is emerging as an exciting treatment option for TNBC patients. The aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer (BC), is overproduced and hypersecreted by human BC cells. This study explores whether cath-D is a tumor cell-associated extracellular biomarker and a potent target for antibody-based therapy in TNBC.MethodsCath-D prognostic value and localization was evaluated by transcriptomics, proteomics and immunohistochemistry in TNBC. First-in-class anti-cath-D human scFv fragments binding to both human and mouse cath-D were generated using phage display and cloned in the human IgG1 λ format (F1 and E2). Anti-cath-D antibody biodistribution, antitumor efficacy and in vivo underlying mechanisms were investigated in TNBC MDA-MB-231 tumor xenografts in nude mice. Antitumor effect was further assessed in TNBC patient-derived xenografts (PDXs).ResultsHigh CTSD mRNA levels correlated with shorter recurrence-free survival in TNBC, and extracellular cath-D was detected in the tumor microenvironment, but not in matched normal breast stroma. Anti-cath-D F1 and E2 antibodies accumulated in TNBC MDA-MB-231 tumor xenografts, inhibited tumor growth and improved mice survival without apparent toxicity. The Fc function of F1, the best antibody candidate, was essential for maximal tumor inhibition in the MDA-MB-231 model. Mechanistically, F1 antitumor response was triggered through natural killer cell activation via IL-15 upregulation, associated with granzyme B and perforin production, and the release of antitumor IFNγ cytokine. The F1 antibody also prevented the tumor recruitment of immunosuppressive tumor-associated macrophages M2 and myeloid-derived suppressor cells, a specific effect associated with a less immunosuppressive tumor microenvironment highlighted by TGFβ decrease. Finally, the antibody F1 inhibited tumor growth of two TNBC PDXs, isolated from patients resistant or not to neo-adjuvant chemotherapy.ConclusionCath-D is a tumor-specific extracellular target in TNBC suitable for antibody-based therapy. Immunomodulatory antibody-based strategy against cath-D is a promising immunotherapy to treat patients with TNBC.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0498-z) contains supplementary material, which is available to authorized users.