Infiltration by CXCL10 Secreting Macrophages Is Associated With Antitumor Immunity and Response to Therapy in Ovarian Cancer Subtypes

Ovarian carcinomas (OCs) are poorly immunogenic and immune checkpoint inhibitors (ICIs) have offered a modest benefit. In this study, high CD3+ T-cells and CD163+ tumor-associated macrophages (TAMs) densities identify a subgroup of immune infiltrated high-grade serous carcinomas (HGSCs) with better outcomes and superior response to platinum-based therapies. On the contrary, in most clear cell carcinomas (CCCs) showing poor prognosis and refractory to platinum, a high TAM density is associated with low T cell frequency. Immune infiltrated HGSC are characterized by the 30-genes signature (OC-IS30) covering immune activation and IFNγ polarization and predicting good prognosis (n = 312, TCGA). Immune infiltrated HGSC contain CXCL10 producing M1-type TAM (IRF1+pSTAT1Y701+) in close proximity to T-cells. A fraction of these M1-type TAM also co-expresses TREM2. M1-polarized TAM were barely detectable in T-cell poor CCC, but identifiable across various immunogenic human cancers. Single cell RNA sequencing data confirm the existence of a tumor-infiltrating CXCL10+IRF1+STAT1+ M1-type TAM overexpressing antigen processing and presentation gene programs. Overall, this study highlights the clinical relevance of the CXCL10+IRF1+STAT1+ macrophage subset as biomarker for intratumoral T-cell activation and therefore offers a new tool to select patients more likely to respond to T-cell or macrophage-targeted immunotherapies

Composition et évolution du manteau lithosphérique nord-africain : évidences pétrologiques et géochimiques à partir des enclaves de manteau échantillonnées par le volcanisme cénozoïque intraplaque du Moyen Atlas (Maroc)

The Ph.D. study is aimed at characterising the composition of pyroxenite xenoliths brought to the surface by Cenozoic intraplate volcanism in the Azrou Timahdite district of Middle Atlas (Morocco) to unravel their origin and significance in the frame of the geodynamic evolution of the North Africa lithospheric mantle. The interpretations are based on a petrological approach and on reliable geochemical information at both bulk rock and mineral scale. The data are used to address a largely debated and crucial issue, namely whether pyroxenites do represent ancient magmatic events or section of subducted crust recycled into the lithospheric mantle. The geochemical data revealed that the Middle Atlas pyroxenites formed through different processes: 1 – recycling of older oceanic crust in the lithospheric mantle; 2 – reactions between mantle melt and older mafic layers; 3 – magmatic crystallization from enriched melts at mantle depth. In an overall geodynamic scenario, the origin and age of the pyroxenites interpreted as fragments of recycled oceanic crust and as products of melt-Rock interaction processes are not completely understood. By analogy with Ronda and Beni Bousera these pyroxenites could represent old mafic rocks that have been isolated in the subcontinental lithospheric mantle for very long time spans. The fragments of oceanic material and the crustal components recorded by pyroxenites may be tentatively related to subduction processes occurred during Pan-African times. If so, these pyroxenites maintained for long time their pristine geochemical signatures without marked changes.Cette étude vise à caractériser la composition chimique d’enclaves de pyroxénites échantillonnées par le volcanisme cénozoïque intraplaque de la province volcanique de Azrou Timahdite dans le Moyen Atlas marocain afin de préciser leur origine et leur signification dans le cadre de l’évolution géodynamique du manteau sous l’Afrique du Nord. Les interprétations sont basées sur une étude pétrologique et sur des données géochimiques à l’échelle de la roche totale et du minéral. Les données sont utilisées dans le cadre du débat récurrent pour savoir si les pyroxénites représentent d’anciens événements magmatiques ou sont des fragments de croûte océanique recyclés dans le manteau lithosphérique. Les données géochimiques montrent que les pyroxénites du Moyen Atlas ont été formées par différents processus : 1 - recyclage de croûte océanique dans le manteau lithosphérique; 2 – réactions entre un magma et des roches basiques anciennes ; 3 – cristallisation dans le manteau à partir d’un magma enrichi. L’origine et l’âge des pyroxénites formées par recyclage de la croûte océanique ou par réaction entre un magma et des roches plus anciennes sont difficile à interpréter dans le cadre de l’évolution géodynamique de cette région. Par analogie avec les massifs de Ronda et de Beni Bousera, ces pyroxénites pourraient représenter d’anciennes roches basiques isolées depuis très longtemps dans le manteau lithosphérique sous-Continental. Ces fragments de croûte océanique et certaines signatures crustales peuvent être reliés à des processus de subduction pan-Africains. Dans ce cas, ces pyroxénites ont gardé leur signature géochimique intacte, sans modification significative au cours du temps

Composition and evolution of the North-African lithospheric mantle : petrological and geochemical evidence from mantle xenoliths sampled by cenozoic intraplate volcanism of the Middle Atlas (Morocco)

Cette étude vise à caractériser la composition chimique d’enclaves de pyroxénites échantillonnées par le volcanisme cénozoïque intraplaque de la province volcanique de Azrou Timahdite dans le Moyen Atlas marocain afin de préciser leur origine et leur signification dans le cadre de l’évolution géodynamique du manteau sous l’Afrique du Nord. Les interprétations sont basées sur une étude pétrologique et sur des données géochimiques à l’échelle de la roche totale et du minéral. Les données sont utilisées dans le cadre du débat récurrent pour savoir si les pyroxénites représentent d’anciens événements magmatiques ou sont des fragments de croûte océanique recyclés dans le manteau lithosphérique. Les données géochimiques montrent que les pyroxénites du Moyen Atlas ont été formées par différents processus : 1 - recyclage de croûte océanique dans le manteau lithosphérique; 2 – réactions entre un magma et des roches basiques anciennes ; 3 – cristallisation dans le manteau à partir d’un magma enrichi. L’origine et l’âge des pyroxénites formées par recyclage de la croûte océanique ou par réaction entre un magma et des roches plus anciennes sont difficile à interpréter dans le cadre de l’évolution géodynamique de cette région. Par analogie avec les massifs de Ronda et de Beni Bousera, ces pyroxénites pourraient représenter d’anciennes roches basiques isolées depuis très longtemps dans le manteau lithosphérique sous-Continental. Ces fragments de croûte océanique et certaines signatures crustales peuvent être reliés à des processus de subduction pan-Africains. Dans ce cas, ces pyroxénites ont gardé leur signature géochimique intacte, sans modification significative au cours du temps.The Ph.D. study is aimed at characterising the composition of pyroxenite xenoliths brought to the surface by Cenozoic intraplate volcanism in the Azrou Timahdite district of Middle Atlas (Morocco) to unravel their origin and significance in the frame of the geodynamic evolution of the North Africa lithospheric mantle. The interpretations are based on a petrological approach and on reliable geochemical information at both bulk rock and mineral scale. The data are used to address a largely debated and crucial issue, namely whether pyroxenites do represent ancient magmatic events or section of subducted crust recycled into the lithospheric mantle. The geochemical data revealed that the Middle Atlas pyroxenites formed through different processes: 1 – recycling of older oceanic crust in the lithospheric mantle; 2 – reactions between mantle melt and older mafic layers; 3 – magmatic crystallization from enriched melts at mantle depth. In an overall geodynamic scenario, the origin and age of the pyroxenites interpreted as fragments of recycled oceanic crust and as products of melt-Rock interaction processes are not completely understood. By analogy with Ronda and Beni Bousera these pyroxenites could represent old mafic rocks that have been isolated in the subcontinental lithospheric mantle for very long time spans. The fragments of oceanic material and the crustal components recorded by pyroxenites may be tentatively related to subduction processes occurred during Pan-African times. If so, these pyroxenites maintained for long time their pristine geochemical signatures without marked changes

Analogues of exhumed pyroxenite layers in the Alboran domain sampled as xenoliths by Middle Atlas Cenozoic volcanism

International audienceThe evolutionary stages of lithospheric mantle in the Alboran domain are recorded by peridotites and associated pyroxenites outcropping in the Betic–Rifean orogenic belt. We show here that the scale of lithospheric mantle interpretation can be extended up to at least 300 km farther south of Beni Bousera thanks to the occurrence in Middle Atlas Cenozoic volcanics of rare pyroxenite mantle xenoliths, which unlike most peridotite xenoliths still preserve their pre-metasomatic geochemical signatures. These pyroxenites closely match mafic layers from Ronda and Beni Bousera occurrences and include, in addition to more common Spl-facies pyroxenites and former Grt-bearing pyroxenites accreted to the lithosphere and equilibrated under Spl-facies condition, also former Pl-bearing cumulates that represent old sectors of delaminated lower crust. The close similarity of Middle Atlas pyroxenite xenoliths to mafic layers in the Alboran domain makes the region comprising the Betic-Rifean belt and Middle Atlas one of the few occurrences that allow petrological and chemical information from exhumed mantle sectors to be combined with that from non-exhumed sectors, which only a few million years later were brought to the surface by volcanic activity

A population of TIM4+FOLR2+ macrophages localized in tertiary lymphoid structures correlates to an active immune infiltrate across several cancer types

TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remains poorly explored. Here we combined extensive immunolabeling of human tissues with in-silico analysis of pan-cancer transcriptomic datasets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (CATIM4+MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (TLSTIM4+MΦ). In-silico analysis of a pan-cancer dataset revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8+ T cells and a 12-chemokine signature defining tertiary lymphoid structure. In addition, TLSTIM4+MΦ were enriched in cancers displaying microsatellite instability and high CD8+ T-cell infiltration, confirming their association with immune-reactive tumors. Both CATIM4+MΦ and TLSTIM4+MΦ express FOLR2, a marker of tissue-resident MΦ. However, CATIM4+MΦ had higher expression of the immunosuppressive molecules TREM2, IL10 and TGFβ as compared to TLSTIM4+MΦ. By analyzing a scRNA-seq dataset of tumor-associated myeloid cells we identified two TIM4+FOLR2+ clusters coherent with CATIM4+MΦ and TLSTIM4+MΦ. We defined specific gene-signatures for each subset and found that the CATIM4+ MΦ signature was associated with worse patient survival. In contrast, TLSTIM4+MΦ gene-signature positively correlate with better prognosis. Together these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotype and tissue localization and that may have opposing roles in tumor immunity